Diabetes-Induced Vascular Dysfunction and Stemness Decline Investigated via Transcription Factor-Driven Genetic Switches

doi:10.21203/rs.3.rs-4498525/v1

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Diabetes-Induced Vascular Dysfunction and Stemness Decline Investigated via Transcription Factor-Driven Genetic Switches

https://doi.org/10.21203/rs.3.rs-4498525/v1

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Background:

Diabetes mellitus precipitates cardiovascular complications through hyperglycemia, oxidative stress, and inflammation, disrupting vascular cell function. This dysfunction involves altered regulation of transcription factors like Nrf2 and FOXP1, leading to endothelial dysfunction, impaired angiogenesis, and faulty vascular remodeling. Additionally, diabetes reduces the stemness of vascular progenitor cells, hampering vascular repair and homeostasis. Understanding these mechanisms is crucial for identifying therapeutic targets to mitigate diabetic vascular complications.

Methods:

Databases, including PubMed, MEDLINE, Google Scholar, and open access/subscription-based journals were searched for published articles without any date restrictions, to investigate the diabetes-induced vascular dysfunction and stemness decline through the lens of vascular transcription factor-driven genetic switches. Based on the criteria mentioned in the methods section, studies were systematically reviewed to investigate how diabetes harms vascular cells. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).

Results:

This study reveals significant dysregulation of key transcription factors including Nrf2, FOXP1, SMAD, PAX3/7, and GATA in diabetes, leading to compromised oxidative stress responses and increased inflammatory signaling in vascular cells. In endothelial cells, impaired function of these factors resulted in decreased nitric oxide production and increased endothelial permeability. Additionally, altered FOXP1 and GATA activity exacerbated vascular inflammation. In VSMCs, diabetes-induced transcription factor dysregulation promoted a shift from a contractile to a synthetic phenotype, characterized by increased proliferation and matrix production, contributing to vascular stiffness and atherosclerosis. The stemness of vascular progenitor cells was notably reduced, affecting their differentiation capabilities and exacerbating vascular complications in diabetic conditions.

Conclusion:

Diabetes impairs vascular health by disrupting key transcription factors and signaling pathways, leading to endothelial dysfunction, abnormal vascular remodeling, and a decline in stemness of vascular cells. Dysregulated factors like Nrf2, FOXP1, and GATA contribute to reduced nitric oxide production, increased vascular permeability, and enhanced inflammation, exacerbating atherosclerosis and hypertension. Addressing these dysfunctions through targeted therapies that enhance transcription factor activity and modulate signaling pathways may mitigate diabetes-related vascular complications. Further research is essential for developing effective interventions to restore vascular homeostasis in diabetic patients.

Cardiac & Cardiovascular Systems

Cardiothoracic Surgery

Diabetes

medicine

vascular stemness

insulin resistance

vascular homeostasis

cardiovascular disease

Diabetes mellitus, a chronic metabolic disorder characterized by hyperglycemia, is known to precipitate a range of systemic complications, particularly cardiovascular diseases, which remain the leading cause of morbidity and mortality among diabetic patients. The vascular complications associated with diabetes stem from complex interactions at the molecular and cellular levels that compromise vascular integrity and function [1]. This underscores the critical need for a deeper understanding of the underlying mechanisms by which diabetes influences vascular cells, including both vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). The pathophysiology of diabetic vascular complications involves persistent hyperglycemia, oxidative stress, and chronic inflammation, all of which contribute to the dysfunction of vascular cells. At the heart of this dysfunction is the altered regulation of critical transcription factors and associated signaling pathways that dictate cell growth, differentiation, survival, and function [2]. The disruption of transcription factors such as Nrf2, FOXP1, PAX3/7, and GATA significantly affects the cellular responses to oxidative stress and inflammation, leading to endothelial dysfunction, impaired angiogenesis, and aberrant vascular remodeling. Furthermore, diabetes is known to affect the 'stemness' of vascular progenitor cells, crucial for maintaining vascular repair mechanisms and endothelial regeneration. The decline in these progenitor cells' functionality exacerbates the inability of the vascular system to repair itself effectively, leading to chronic complications and impaired vascular homeostasis [3]. The investigation into how diabetes-induced changes impact these critical transcription factors and signaling pathways provides essential insights into the cascading effects of diabetes on vascular health. Understanding these molecular dynamics is paramount, not only for delineating the pathogenic processes that lead to vascular complications in diabetes but also for identifying potential therapeutic targets [4]. This research aims to bridge gaps in knowledge regarding the molecular etiology of diabetic vascular diseases and to explore novel intervention strategies that could mitigate these severe complications, ultimately enhancing patient outcomes and quality of life [5].

PUBMED database, MEDLINE database, Google Scholar and open access/subscription-based journals were searched with no date restrictions for published articles. The following vascular transcription factor-driven genetic switches were investigated to look into the diabetes-induced vascular dysfunction and stemness decline:

HIF-1α, KLFs, NF-κB, NOTCH Signaling Transcription Factors, AP-1, ETS Family Transcription Factors, FOXC Transcription Factors, GATA Transcription Factors, SMAD Transcription Factors, Nrf2, PAX3/7, FOXP1.

They were investigated to determine: diabetes-induced disruption of vascular cell fate, damage to downstream regulators of the insulin receptor (PI3K, AKT, mTOR, and FOXO) in vascular cells, and diabetes-induced damage disrupting homeostasis in vascular cells.

The primary objective of this study is to elucidate how diabetes induces dysfunction in vascular cells and leads to a decline in the stemness of these cells, ultimately resulting in compromised vascular homeostasis.

Screening of the literature was also done on this same basis and related data was extracted. Literature search began in November 2020 and ended in October 2023. An in-depth investigation was conducted during this duration based on the parameters of the study as defined above. During revision, further literature was searched and referenced until April 2024. The literature search and all sections of the manuscript were checked multiple times during the months of revision (November 2023 – April 2024) to maintain the highest accuracy possible. The prime focus of the literature search was to screen the literature on the basis of eligibility criteria mentioned above. It employs PRISMA guidelines as a tool for the investigation. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Publications only in ‘English’ were used and there was no limitation on date of publication. Data extraction was based on these eligibility criteria. Studies were systematically reviewed based on the criteria mentioned in the methods section. No unpublished study was used or included.

A total of 2618 articles were identified using database searching, and 2315 were recorded after duplicates removal. 1953 were excluded after screening of title/abstract, 159 were finally excluded, and 5 articles were excluded during data extraction. Finally, 198 articles were included as references.

Overview of the Study:
This study investigates the impact of diabetes on several critical transcription factors and their downstream effects on the homeostasis of vascular cells. Through detailed investigation, it explores how diabetes-induced dysregulations of these transcription factors lead to vascular endothelial and smooth muscle cell dysfunction, a decline in vascular stemness, and overall deterioration of vascular health. Hypoxia-Inducible Factor 1-alpha (HIF-1α), crucial for the cellular response to hypoxia, becomes dysregulated under diabetic conditions, affecting vascular adaptation to hypoxic environments and impairing angiogenesis. This dysregulation contributes to poor tissue repair and increased susceptibility to ischemic conditions. Krüppel-Like Factors (KLFs) are vital for maintaining endothelial barrier function and vascular tone. Diabetes impairs these factors, leading to endothelial dysfunction, increased vascular permeability, and accelerated atherosclerosis progression. Chronic inflammation induced by diabetes activates Nuclear Factor-kappa B (NF-κB), promoting the expression of pro-inflammatory genes and exacerbating vascular inflammation, thereby contributing to the pathogenesis of vascular diseases. NOTCH signaling, essential for the differentiation and maintenance of vascular cells, is disrupted by diabetes, leading to altered vascular cell fate decisions and abnormal vascular remodeling. Activator Protein-1 (AP-1), responsive to oxidative stress, becomes overly active in diabetes, leading to increased expression of inflammatory mediators and further damaging vascular endothelial integrity. Dysregulation of ETS family transcription factors in diabetes impairs their ability to regulate genes critical for endothelial function and smooth muscle cell behavior, contributing to vascular stiffness and endothelial barrier dysfunction. FOXC transcription factors, which play a role in developmental processes and cell differentiation, are compromised in diabetes, affecting the structural and functional integrity of vascular cells. Diabetes-induced alterations in GATA transcription factors affect their control over vascular smooth muscle cell phenotype and function, leading to pathological vascular remodeling and hypertension. SMAD proteins, which mediate TGF-β signaling, are crucial for vascular cell repair and fibrosis. Their dysfunction in diabetes promotes fibrotic processes and impairs healing, exacerbating diabetic vascular complications. Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) is critically undermined in diabetes, leading to increased oxidative stress and vascular damage as its role in regulating antioxidant defense mechanisms is compromised. Diabetes impairs the function of PAX (Paired Box) transcription factors PAX3/7, crucial for the regenerative capacity of vascular progenitor cells, thereby diminishing the vascular repair mechanisms essential in managing chronic vascular injuries. FOXP1 (Forkhead Box Protein P1), essential for the proper growth and differentiation of vascular cells, is impaired in diabetes, leading to dysfunctional endothelial and smooth muscle cells, contributing to overall vascular dysfunction.
This study looks into the vascular dysfunction/stemness decline associated with both Type 1 Diabetes Mellitus (DM1) and Type 2 Diabetes Mellitus (DM2), encompassing a broad spectrum of diabetes-induced challenges to vascular health. Both forms of diabetes, despite their distinct pathophysiological origins, share common detrimental effects on vascular cells, including endothelial cells and vascular smooth muscle cells. The study focuses also on the dysfunctions induced by chronic hyperglycemia, which is a hallmark of both DM1 and DM2. These include the disruption of critical transcription factors and signaling pathways that govern vascular cell integrity, function, and regenerative capacity. By investigating the impacts of diabetes on these fundamental processes, the study provides insights that are applicable to understanding and mitigating vascular complications across both types of diabetes, thus offering a holistic approach to tackling diabetes-related vascular complications.

Investigating Vascular Transcription Factor-Driven Genetic Switches:

1. HIF-1α
Diabetes-Induced Disruption of Vascular Cell Fate:
Hypoxia-Inducible Factor 1-alpha (HIF-1α) is a crucial transcription factor that plays a central role in cellular responses to hypoxia. In the context of vascular biology, HIF-1α regulates various processes including angiogenesis, cellular survival, metabolism, and vascular remodeling. It is particularly important in the function and fate of vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs), both of which are critical components of the vascular system. In diabetes, the chronic hyperglycemic state can induce a myriad of changes that affect HIF-1α expression and function [6]. Hyperglycemia leads to increased production of Reactive Oxygen Species (ROS), which can stabilize HIF-1α under normoxic conditions by inhibiting prolyl hydroxylases (PHDs) that normally degrade HIF-1α. Although initially this may seem beneficial, chronic dysregulation can lead to aberrant expression of HIF-1α target genes, contributing to pathological angiogenesis or fibrosis. The non-enzymatic glycation of proteins, a hallmark of diabetes, can affect proteins involved in the HIF-1α degradation pathway or those that modulate its activity, potentially leading to altered stability and function of HIF-1α. Additionally, diabetes modifies cellular metabolism, which can impact the pathways that regulate HIF-1α, including those mediated by PHDs and von Hippel-Lindau (VHL) protein that targets HIF-1α for degradation. In vascular cells, dysregulated HIF-1α has significant consequences [7]. In endothelial cells, HIF-1α promotes the expression of angiogenic factors such as VEGF (Vascular Endothelial Growth Factor). In diabetes, dysregulated HIF-1α activity can lead to abnormal angiogenesis, characteristic of diabetic retinopathy and other microvascular complications. HIF-1α also influences the expression of proteins involved in maintaining endothelial barrier integrity. Dysregulation could lead to increased vascular permeability, a common issue in diabetic vascular complications. Prolonged or excessive HIF-1α activation in diabetes may promote Endothelial-to-Mesenchymal Transition, contributing to fibrosis and thickening of the vascular walls, commonly observed in diabetic cardiomyopathy and nephropathy. For vascular smooth muscle cells (VSMCs), HIF-1α can promote VSMC proliferation and migration, processes involved in vascular remodeling. Dysregulated HIF-1α expression in diabetes may contribute to pathological vascular remodeling, leading to vascular stiffness and atherosclerosis [8]. HIF-1α modulates the expression of several contractile proteins in VSMCs. Abnormal regulation in diabetes can affect vascular tone and responsiveness, leading to hypertension and impaired vascular function. Potential therapeutic approaches include targeting HIF-1α directly, where small molecule inhibitors or stabilizers of HIF-1α could be developed to correct the abnormal activity of HIF-1α in diabetic vascular cells. Antioxidant therapy that reduces ROS levels could indirectly regulate HIF-1α stabilization and activity, potentially mitigating its pathological activation in diabetes. Metabolic modulators, such as drugs that modulate metabolism (e.g., metformin), could also affect HIF-1α regulation by altering the cellular metabolic state and reducing hyperglycemia-driven alterations [9].
Damage to Downstream Regulators of the Insulin Receptor (PI3K, AKT, mTOR, and FOXO) in Vascular Cells:
Diabetes-induced damage to HIF-1α can significantly influence the downstream regulators of the insulin receptor, notably the PI3K/AKT/mTOR and FOXO pathways, in both vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) [10]. These pathways are crucial for maintaining cellular homeostasis, growth, survival, and metabolism. Dysregulation in these pathways due to aberrant HIF-1α activity can lead to various pathological changes. In vascular endothelial cells (VECs), normally, HIF-1α upregulates VEGF, promoting angiogenesis via the PI3K/AKT pathway [11]. However, in diabetes, if HIF-1α is dysregulated, this can lead to inappropriate activation or suppression of the PI3K/AKT pathway, resulting in either excessive or insufficient angiogenesis. This dysregulation is a key feature in diabetic retinopathy and other microvascular complications. The integrity of the endothelial barrier is partially maintained by signaling through PI3K/AKT, which influences tight junction proteins and endothelial nitric oxide synthase (eNOS) activity [12]. Abnormal HIF-1α levels can disrupt this pathway, leading to increased vascular permeability and endothelial dysfunction. In vascular smooth muscle cells (VSMCs), PI3K/AKT signaling promotes the proliferation and migration of VSMCs, processes crucial for vascular remodeling. Dysregulated HIF-1α, as seen in diabetes, could aberrantly enhance or inhibit these processes, contributing to pathological vascular remodeling, atherosclerosis, and restenosis [13]. The PI3K/AKT pathway also regulates VSMC contraction and relaxation by modulating calcium handling and sensitivity. Dysregulation due to altered HIF-1α activity can impair vascular tone and reactivity, leading to hypertension and vascular stiffness. Regarding FOXO transcription factors, in vascular endothelial cells, FOXO factors are involved in regulating apoptosis, cell cycle arrest, and oxidative stress response. Diabetes-induced alterations in HIF-1α could disrupt normal FOXO activity through skewed PI3K/AKT signaling, enhancing oxidative stress and susceptibility to apoptosis, contributing to endothelial cell damage and diabetic vascular complications. FOXO transcription factors upregulate the expression of genes involved in antioxidant defense. Dysfunctional HIF-1α may impair this response by altering FOXO activity, further exacerbating oxidative stress and endothelial dysfunction in diabetes. In vascular smooth muscle cells, FOXO factors regulate several aspects of VSMC behavior, including senescence and autophagy. Dysregulation of HIF-1α could lead to inappropriate activation or inhibition of FOXO, disrupting these processes and contributing to the aging of vascular cells and pathological vascular remodeling. [14] FOXO factors also play a role in metabolic regulation within VSMCs. Dysfunctional signaling induced by altered HIF-1α activity could result in metabolic disturbances, contributing to the development of vascular complications. Understanding how diabetes-induced changes in HIF-1α affect these critical pathways can lead to targeted therapeutic strategies, including HIF-1α stabilizers or inhibitors to help normalize PI3K/AKT/mTOR and FOXO signaling, restoring proper vascular function. Direct targeting of PI3K/AKT/mTOR or FOXO using inhibitors or activators could mitigate the vascular effects of diabetes. Additionally, since oxidative stress is both a cause and consequence of these pathway dysregulations, antioxidants could help restore normal function. This complex interplay underscores the importance of a systemic approach in the treatment of diabetic vascular complications, focusing on both upstream regulators like HIF-1α and the downstream effects on critical signaling pathways within vascular cells [15].
Diabetes-Induced Damage Disrupting Homeostasis in Vascular Cells:
Diabetes-induced damage to Hypoxia-Inducible Factor 1-alpha (HIF-1α) can have widespread and significant implications for the homeostasis of vascular cells [16]. The disruption primarily stems from the central role HIF-1α plays in responding to hypoxic conditions and regulating a variety of cellular processes, including angiogenesis, metabolism, and survival. HIF-1α typically induces the expression of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis. In diabetes, if HIF-1α is either overactive due to chronic hypoxic signaling or underactive due to oxidative damage, the result can be either uncontrolled or insufficient angiogenesis. Excessive angiogenesis can lead to fragile blood vessels as seen in diabetic retinopathy, while insufficient angiogenesis can impair wound healing, a common complication in diabetes. Additionally, HIF-1α influences the proliferation and migration of vascular smooth muscle cells (VSMCs) [17]. Aberrant activation in diabetes might contribute to pathological vascular remodeling and increased vascular stiffness, which are risk factors for hypertension and atherosclerosis. HIF-1α plays a critical role in adapting cellular metabolism under hypoxic conditions, including switching from aerobic to anaerobic glucose metabolism [18]. Dysregulation due to diabetes may result in inefficient energy utilization and exacerbate metabolic disturbances in vascular cells, further stressing the cells and potentially leading to metabolic dysfunction. HIF-1α is essential for enabling cells to cope with low oxygen levels. Diabetes-induced damage to HIF-1α could impair this adaptive response, making vascular cells less capable of surviving in hypoxic conditions, such as those found in ischemic tissues [19]. Under normal conditions, HIF-1α can upregulate antioxidants and protective enzymes. If its function is compromised by diabetes, this could lead to an inability to effectively combat oxidative stress, further damaging vascular cells and contributing to endothelial dysfunction. Dysregulated HIF-1α activity can also affect the expression of inflammatory cytokines and adhesion molecules in endothelial cells. This can enhance leukocyte adhesion and vascular inflammation, worsening the inflammatory milieu typically seen in diabetes [20]. The balance of vasodilators and vasoconstrictors, crucial for endothelial function, can be disrupted by altered HIF-1α signaling. For example, reduced expression of nitric oxide synthase (NOS) and increased endothelin-1 could contribute to vasoconstriction and hypertension. Given the key role of HIF-1α in vascular homeostasis, targeting this transcription factor or its downstream pathways offers a promising therapeutic avenue. Strategies might include antioxidant therapy to reduce oxidative damage and restore normal HIF-1α function, pharmacological modulation of HIF-1α activity either through stabilization of its expression under diabetic conditions or inhibition where overactivity leads to detrimental outcomes, and gene therapy approaches to correct dysfunctional HIF-1α signaling specifically in vascular cells [21]. Continued research is necessary to fully understand the multidimensional roles of HIF-1α in diabetes-induced vascular dysfunction and to develop interventions that can precisely modulate this pathway to restore vascular health without adverse effects [22].

2. Krüppel-like factors (KLFs)
Diabetes-Induced Disruption of Vascular Cell Fate:
Krüppel-like factors (KLFs) are a family of transcription factors that play crucial roles in regulating various cellular processes, including differentiation, proliferation, apoptosis, and response to environmental signals. In the vascular system, specific KLFs, such as KLF2, KLF4, and KLF15, are important for the maintenance and function of both vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) [23]. Their roles in vascular biology include influencing endothelial nitric oxide synthase (eNOS) expression, controlling blood vessel tone, and regulating inflammatory responses, which are vital for maintaining vascular homeostasis. Diabetes can lead to dysregulation of KLFs through several mechanisms [24]. Chronic high glucose levels can alter the expression and function of KLFs, with KLF2 and KLF4 known to be downregulated in hyperglycemic conditions, which affects the anti-inflammatory and anti-thrombotic properties of endothelial cells. Increased oxidative stress in diabetes can modify signaling pathways that control KLF expression and activity, often leading to the activation of pathways that inhibit KLF function. Additionally, diabetes-associated inflammation can alter the expression levels of KLFs, such as inflammatory cytokines suppressing KLF2 in endothelial cells, contributing to endothelial dysfunction. In vascular endothelial cells (VECs), dysregulation of KLF2 and KLF4 can lead to reduced nitric oxide (NO) production, enhanced endothelial permeability, and increased vascular inflammation, contributing to endothelial dysfunction [25]. KLF factors are also involved in the regulation of angiogenesis. Altered expression of KLFs in diabetes may impair the ability of endothelial cells to form new blood vessels, which is critical in wound healing and responding to ischemic conditions. In vascular smooth muscle cells (VSMCs), KLFs regulate the contractile phenotype of VSMCs. In diabetes, changes in KLF expression can lead to a shift towards a more synthetic phenotype, characterized by increased cell proliferation, migration, and extracellular matrix production. This phenotypic switch contributes to vascular stiffness and atherosclerotic plaque development. KLF4, in particular, has anti-inflammatory properties in VSMCs [26]. Dysregulation can increase the expression of inflammatory markers and adhesion molecules, promoting the recruitment of immune cells and development of atherosclerotic lesions. Given the role of KLFs in maintaining vascular cell function and integrity, targeting these transcription factors or their regulatory pathways offers a promising strategy for managing diabetic vascular complications. Approaches such as gene therapy, introducing or enhancing the expression of beneficial KLFs like KLF2 and KLF4, could help restore endothelial function and reduce atherosclerotic risk. Drug development aimed at small molecules or biologics that can modulate KLF activity may serve as therapeutic agents to improve vascular health in diabetic patients. Since oxidative stress and inflammation can suppress the beneficial effects of KLFs, therapies aimed at reducing these stressors could indirectly promote KLF activity. Continued research into the specific mechanisms by which diabetes impacts KLF function in vascular cells will be crucial [27].
Damage to Downstream Regulators of the Insulin Receptor (PI3K, AKT, mTOR, and FOXO) in Vascular Cells:
Diabetes-induced damage to Krüppel-like factors (KLFs) can have profound effects on the regulation of downstream pathways of the insulin receptor, particularly the PI3K/AKT/mTOR and FOXO pathways in vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) [28]. These pathways are integral to maintaining cellular homeostasis, mediating responses to insulin, controlling cell survival, growth, metabolism, and angiogenesis. In vascular endothelial cells, KLFs, especially KLF2 and KLF4, enhance the expression of eNOS and promote nitric oxide (NO) production through the PI3K/AKT pathway. Impaired KLF function due to diabetes could reduce PI3K/AKT signaling efficiency, diminishing NO production and contributing to endothelial dysfunction. Additionally, KLFs regulate VEGF expression and thus play a role in angiogenesis through the PI3K/AKT pathway. Dysregulation of KLFs in diabetes might lead to inadequate angiogenic responses, affecting wound healing and tissue repair processes, which are often compromised in diabetic patients [29]. Under normal conditions, FOXO factors are negatively regulated by the AKT pathway, which phosphorylates FOXO, leading to its exclusion from the nucleus and inhibition of its transcriptional activity. Dysregulated KLF activity can alter PI3K/AKT signaling, potentially leading to inappropriate activation or inhibition of FOXO. This may impact the cell’s ability to manage oxidative stress and survive under diabetic conditions. In vascular smooth muscle cells, KLFs regulate the contractile phenotype of VSMCs. Dysregulation of KLFs could lead to altered PI3K/AKT signaling, promoting a synthetic phenotype associated with increased proliferation and migration [30]. This phenotypic shift is crucial in the development of vascular diseases such as atherosclerosis, commonly exacerbated by diabetes. In diabetes, VSMCs often exhibit altered insulin signaling, leading to impaired glucose uptake and metabolism. Since KLFs influence the expression of several components involved in insulin signaling, their dysregulation could further impair these processes. Altered PI3K/AKT signaling resulting from KLF dysregulation might lead to changes in FOXO activity, affecting the expression of genes involved in metabolism, apoptosis, and proliferation in VSMCs [31]. Dysfunctional FOXO activity can contribute to metabolic abnormalities and increased susceptibility to cell death, which are critical in the progression of diabetic vascular complications. Strategies to enhance the expression or function of KLFs in vascular cells could help restore proper signaling through PI3K/AKT/mTOR and FOXO pathways, improving vascular function and reducing complications. Given their central role in mediating the effects of KLFs in diabetes, direct modulation of these pathways could also be beneficial, especially in counteracting the effects of diabetes-induced KLF dysregulation. Using a combination of therapies that target both the modulation of KLF activity and direct regulation of downstream insulin signaling pathways may provide a synergistic effect, improving overall vascular health in diabetic patients. Further research into these pathways could lead to more targeted and effective treatments for diabetes-associated vascular complications [32].
Diabetes-Induced Damage Disrupting Homeostasis in Vascular Cells:
Diabetes-induced damage to Krüppel-like factors (KLFs) can significantly disrupt the homeostasis of vascular cells, leading to a variety of vascular complications. KLFs, including KLF2, KLF4, and others, play crucial roles in maintaining endothelial integrity, regulating smooth muscle cell phenotype, and controlling inflammatory responses within the vascular system [33]. Particularly, KLF2 and KLF4 promote endothelial nitric oxide synthase (eNOS) expression and activity, leading to nitric oxide (NO) production, which is critical for vascular tone regulation and endothelial barrier function. Diabetes-induced downregulation or dysfunction of these KLFs results in decreased NO levels, contributing to endothelial dysfunction, a key factor in the development of atherosclerosis and hypertension. KLFs also enhance the expression of tight junction proteins and adherence junctions which are vital for endothelial barrier integrity. Dysfunctional KLF expression weakens these barriers, increasing vascular permeability, which can exacerbate edema and promote the infiltration of inflammatory cells into the vessel wall. KLF2 and KLF4 have anti-inflammatory properties in vascular endothelial cells by inhibiting the expression of adhesion molecules (such as VCAM-1 and ICAM-1) and cytokines [34]. Impaired function of these transcription factors in diabetes can lead to heightened vascular inflammation, a precursor to various vascular diseases including atherosclerosis. KLFs regulate the expression of several angiogenic factors, including VEGF. Diabetes-induced alterations in KLF expression or function can lead to either insufficient or excessive angiogenesis. Inadequate angiogenesis impairs wound healing, a common complication in diabetes, whereas uncontrolled angiogenesis contributes to the proliferation of unstable microvessels seen in diabetic retinopathy. In vascular smooth muscle cells (VSMCs), KLF4 in particular helps maintain the contractile phenotype [35]. Diabetes-induced dysfunction of KLF4 can shift VSMCs to a synthetic phenotype, characterized by increased proliferation, migration, and secretion of extracellular matrix components. This phenotypic transition is crucial in vascular remodeling and the progression of atherosclerosis. Diabetes alters the response of VSMCs to injury, partially mediated by changes in KLF expression. Dysfunctional repair mechanisms can lead to abnormal neointima formation, contributing to stenosis and ischemic complications. Some KLFs are involved in metabolic regulation within vascular cells [36]. Dysregulation of these factors in diabetes can further impair cellular metabolism, exacerbating hyperglycemic damage and lipid abnormalities within the vascular wall. Enhancing or restoring the function of KLFs in diabetic patients could be a potential therapeutic strategy to mitigate endothelial dysfunction, reduce inflammation, normalize angiogenesis, and prevent the phenotypic switch of VSMCs. Utilizing gene therapy to increase the expression of specific KLFs or developing small molecule modulators that can enhance their activity or mimic their effects could provide new avenues for treating diabetes-induced vascular complications [37].

3. NF-κB
Diabetes-Induced Disruption of Vascular Cell Fate:
Nuclear Factor-kappa B (NF-κB) is a critical transcription factor involved in various cellular processes including inflammation, immune response, cell survival, and proliferation. In the context of vascular biology, NF-κB plays a significant role in mediating the response of vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) to stressors such as cytokines, growth factors, and oxidative stress [38]. Diabetes, particularly through its characteristic chronic hyperglycemia and associated oxidative stress, can lead to persistent activation of NF-κB. This continuous activation has various implications for the vascular system, including increased oxidative stress where hyperglycemia promotes the production of reactive oxygen species (ROS), which can activate NF-κB. NF-κB activation further induces the expression of genes involved in generating oxidative stress, creating a vicious cycle that exacerbates cellular damage [39]. NF-κB is a key regulator of inflammation, and in diabetes, the persistent activation of NF-κB leads to increased transcription of pro-inflammatory cytokines (such as TNF-α, IL-6) and adhesion molecules (such as VCAM-1 and ICAM-1). This can promote the recruitment of immune cells to the vascular wall, contributing to inflammation and the progression of vascular diseases. In vascular endothelial cells (VECs), chronic activation of NF-κB leads to a pro-inflammatory state, reducing the availability of nitric oxide and promoting endothelial dysfunction, a precursor to atherosclerosis [40]. While NF-κB can promote angiogenesis in certain contexts, in a diabetes its dysregulation can lead to abnormal angiogenic responses. This includes the inappropriate formation of new blood vessels, which are often fragile and dysfunctional, a common issue in diabetic retinopathy. NF-κB activation increases the expression of molecules that disrupt tight junctions, enhancing vascular permeability which can lead to vascular leakage and edema [41]. In vascular smooth muscle cells (VSMCs), NF-κB activation promotes a shift from a contractile to a synthetic phenotype, characterized by increased proliferation and migration. This is important in vascular remodeling and the development of atherosclerosis. Activated VSMCs produce excessive extracellular matrix components, contributing to the thickening of the vascular wall and reduction in vessel elasticity, key factors in hypertension and atherosclerosis [42]. Given the role of NF-κB in the pathophysiology of diabetic vascular complications, targeting this pathway offers potential therapeutic benefits. Several inhibitors of NF-κB are under investigation for their potential to reduce inflammation and protect against endothelial dysfunction. For example, salsalate (a drug used to treat inflammation) and other specific NF-κB pathway inhibitors could mitigate vascular inflammation and oxidative stress in diabetes. Reducing oxidative stress can indirectly diminish NF-κB activation. Antioxidants may help restore normal NF-κB activity, thereby reducing the inflammatory and oxidative stress responses in vascular cells [43]. Lifestyle modifications such as diet and exercise have been shown to influence NF-κB activity. Lifestyle interventions that reduce hyperglycemia and improve insulin sensitivity may decrease NF-κB activation and its downstream effects, offering a comprehensive approach to managing and potentially alleviating diabetic vascular complications [44].
Damage to Downstream Regulators of the Insulin Receptor (PI3K, AKT, mTOR, and FOXO) in Vascular Cells:
Diabetes-induced damage involving the activation of Nuclear Factor-kappa B (NF-κB) has significant implications for downstream signaling pathways of the insulin receptor, particularly affecting the PI3K/AKT/mTOR and FOXO pathways in vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) [45]. NF-κB is a key mediator of inflammatory responses, and its chronic activation in diabetes can disrupt normal cellular functions by influencing these critical metabolic and survival pathways. In vascular endothelial cells (VECs), NF-κB-driven inflammatory cytokine production can impair PI3K/AKT signaling, crucial for endothelial cell survival and function. Impaired PI3K/AKT signaling reduces nitric oxide (NO) production by affecting endothelial nitric oxide synthase (eNOS) activity, leading to endothelial dysfunction, a hallmark of diabetic vascular complications [46]. NF-κB can also influence the expression of angiogenic factors like VEGF. However, chronic inflammation might disrupt the normal PI3K/AKT-mediated response to VEGF, leading to dysfunctional angiogenesis, which is particularly relevant in conditions like diabetic retinopathy. In vascular smooth muscle cells (VSMCs), NF-κB activation can lead to the overexpression of inflammatory mediators and adhesion molecules, contributing to the migration and proliferation of VSMCs [47]. This is mediated through alterations in the PI3K/AKT pathway, promoting a synthetic phenotype conducive to plaque formation and vascular stiffening. Chronic inflammation mediated by NF-κB might contribute to insulin resistance in vascular tissues by interfering with insulin signaling through the PI3K/AKT pathway. This disruption can exacerbate metabolic dysregulation within vascular walls, contributing further to vascular disease. NF-κB-induced pro-inflammatory states can antagonistically affect FOXO activity, which is involved in apoptosis, cell cycle regulation, and oxidative stress response [48]. Dysregulated FOXO activity due to impaired AKT signaling (itself influenced by NF-κB-driven inflammation) can lead to increased apoptosis and reduced cell survival. FOXO transcription factors also regulate the expression of genes involved in managing oxidative stress. Dysfunctional FOXO activity, as a result of impaired PI3K/AKT signaling, reduces the cellular capacity to detoxify reactive oxygen species, worsening endothelial damage in diabetes. Inflammatory environments fostered by NF-κB can disrupt the normal function of FOXO factors, accelerating cellular aging processes and contributing to the senescence of VSMCs. This affects vascular elasticity and can promote the development of age-related vascular pathologies. Impaired FOXO function in the context of diabetes and inflammation may lead to further metabolic disturbances in VSMCs, impacting cellular energy use and contributing to the pathological changes associated with vascular complications of diabetes [49]. Targeting NF-κB and its downstream effects on the PI3K/AKT/mTOR and FOXO pathways presents a potential therapeutic strategy to mitigate vascular complications in diabetes. This could involve reducing NF-κB activity with NF-κB inhibitors to alleviate chronic inflammation and restore normal signaling through PI3K/AKT and FOXO, direct modulation of the PI3K/AKT/mTOR pathway to support endothelial function, reduce VSMC proliferation, and improve insulin sensitivity, and using antioxidants and anti-inflammatory agents to reduce the oxidative stress and inflammation that exacerbate NF-κB activity and its downstream effects. This integrated approach to managing NF-κB activity and its impact on vital insulin signaling pathways could help in developing comprehensive treatments for the vascular dysfunction commonly observed in diabetic patients [50].
Diabetes-Induced Damage Disrupting Homeostasis in Vascular Cells:
Diabetes-induced activation and damage to Nuclear Factor-kappa B (NF-κB) can significantly disrupt the homeostasis of vascular cells, playing a key role in the regulation of immune and inflammatory responses. Its activation is a common pathological feature in diabetes, largely due to the chronic inflammatory and oxidative stress states associated with this condition [51]. The implications of NF-κB dysregulation in vascular cells—particularly in vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs)—span various aspects of vascular function and integrity. In endothelial cells, NF-κB drives the expression of pro-inflammatory cytokines such as TNF-α and IL-6, chemokines, and adhesion molecules like VCAM-1 and ICAM-1. This enhances the recruitment and adhesion of leukocytes to the endothelial surface, promoting inflammation and contributing to the early stages of atherosclerotic plaque formation. In VSMCs, NF-κB activation leads to the production of cytokines and growth factors that foster a pro-inflammatory environment within the vascular wall, contributing to the structural remodeling of blood vessels and promoting the progression of atherosclerosis [52]. Chronic activation of NF-κB impairs endothelial production of nitric oxide (NO), a critical vasodilator, by downregulating endothelial nitric oxide synthase (eNOS) expression and function. This results in reduced vasodilation, increased vascular tone, and elevated blood pressure, common features in diabetic vascular disease. NF-κB activation also disrupts the integrity of the endothelial barrier, increasing vascular permeability which can lead to plasma protein extravasation, edema, and further exacerbation of tissue inflammation [53]. In VSMCs, NF-κB influences the phenotypic switching from a contractile to a synthetic phenotype characterized by increased cell proliferation, migration, and the production of extracellular matrix components. This contributes to vascular stiffness and reducing compliance. The synthetic phenotype of VSMCs, driven by NF-κB, also contributes to the development of atherosclerotic plaques by depositing collagen and other matrix proteins that form the basis of plaque structure. Although NF-κB can promote the expression of angiogenic factors like VEGF under certain conditions, chronic and dysregulated activation in diabetes often leads to aberrant angiogenesis. This contributes to the formation of unstable and leaky vessels, particularly problematic in proliferative diabetic retinopathy [54]. Furthermore, NF-κB activation increases the production of reactive oxygen species (ROS) within vascular cells. Elevated ROS levels exacerbate oxidative stress, further activating NF-κB in a vicious cycle, and damaging cellular proteins, lipids, and DNA. Given the central role of NF-κB in mediating many of the pathological changes seen in diabetic vasculopathy, targeting this pathway offers potential for therapeutic intervention. Direct inhibition of NF-κB can potentially reduce inflammation, protect endothelial function, and prevent excessive vascular remodeling. Use of antioxidants to reduce oxidative stress could indirectly decrease NF-κB activation, mitigating its pathological effects [55]. Lifestyle and dietary interventions aimed at reducing systemic inflammation and improving metabolic control can also decrease NF-κB activation, helping to restore vascular homeostasis [56].

4. NOTCH Signaling Transcription Factors
Diabetes-Induced Disruption of Vascular Cell Fate:
The NOTCH signaling pathway is integral to vascular development and plays a critical role in the regulation of cell fate decisions in both vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). This pathway influences cellular processes such as proliferation, differentiation, and apoptosis [57]. Dysregulation of NOTCH signaling is implicated in numerous vascular disorders, and in the context of diabetes, aberrant NOTCH signaling can have profound effects on vascular homeostasis and function [58]. Diabetes can influence NOTCH signaling through several mechanisms: Chronic high blood sugar levels can lead to the glycation of proteins and lipids, potentially modifying NOTCH receptors and their ligands, which could alter their function and disrupt normal signaling. Increased oxidative stress in diabetes can damage cellular components, including NOTCH pathway proteins, potentially altering their function and leading to aberrant signaling [59]. The pro-inflammatory milieu commonly associated with diabetes can modulate NOTCH signaling, either enhancing or inhibiting the pathway in ways that disrupt normal cellular responses. In vascular endothelial cells, NOTCH signaling is important for maintaining endothelial cell identity and function. Dysregulated NOTCH signaling in diabetes may contribute to endothelial dysfunction, a hallmark of diabetic vascular disease, by affecting the expression of genes involved in maintaining barrier integrity and promoting inflammation. NOTCH also plays a role in the regulation of angiogenesis, influencing the sprouting and branching of new blood vessels [60]. Dysregulated NOTCH signaling in diabetes can lead to either insufficient or excessive angiogenic responses, both of which are problematic. Inadequate angiogenesis can impair wound healing, while excessive, disorganized angiogenesis can contribute to complications such as diabetic retinopathy. In vascular smooth muscle cells, NOTCH signaling influences the differentiation state. In diabetes, altered NOTCH signaling might contribute to phenotypic switching from a contractile to a synthetic phenotype, characterized by increased proliferation, migration, and secretion of extracellular matrix proteins [61]. This phenotypic switch is associated with vascular stiffness and atherosclerosis. Disrupted NOTCH signaling can also lead to abnormal VSMC behavior, contributing to pathological vascular remodeling and the progression of vascular diseases, such as atherosclerosis and restenosis after vascular interventions. Given the role of NOTCH in vascular cell fate and function, targeting this pathway may offer new therapeutic avenues for the management of diabetic vascular complications. Modulators of NOTCH signaling, such as gamma-secretase inhibitors which prevent NOTCH receptor activation, could be explored for their potential to normalize vascular cell behavior in diabetes [62]. Therapeutic strategies could also aim to stabilize or mimic the effects of NOTCH ligands, potentially normalizing NOTCH signaling in vascular tissues affected by diabetes. Since inflammation and oxidative stress can exacerbate NOTCH dysregulation, targeting these pathways might indirectly improve NOTCH signaling fidelity, thereby helping to restore normal vascular function. Further research into how diabetes specifically alters NOTCH signaling in vascular cells will help to clarify the mechanisms underlying these changes and to develop targeted interventions that can prevent or reverse the vascular complications associated with diabetes [63].
Damage to Downstream Regulators of the Insulin Receptor (PI3K, AKT, mTOR, and FOXO) in Vascular Cells:
Diabetes-induced damage to the NOTCH signaling pathway can have extensive downstream effects on critical regulators of the insulin receptor pathway, such as PI3K, AKT, mTOR, and FOXO. These effects are significant in vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs), impacting a range of functions from cellular metabolism to survival and proliferation [64]. NOTCH signaling is crucial for maintaining endothelial function and integrity. Dysregulation can lead to altered PI3K/AKT signaling, which is vital for endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production. Impaired NO production results in diminished endothelial-dependent vasodilation and contributes to vascular stiffness and hypertension, common complications in diabetes. NOTCH directly influences angiogenesis, and its interaction with the VEGF signaling pathway often operates via PI3K/AKT. Abnormal NOTCH activity may disrupt normal angiogenic responses, affecting wound healing and promoting aberrant vessel formation, as seen in diabetic retinopathy [65]. In vascular smooth muscle cells (VSMCs), NOTCH signaling can promote the proliferation and survival of VSMCs through the PI3K/AKT pathway. Diabetes-induced NOTCH dysregulation could therefore lead to uncontrolled VSMC growth, contributing to vascular remodeling and atherosclerotic plaque stability. Dysfunctional NOTCH signaling may influence the synthetic versus contractile phenotype of VSMCs through mechanisms involving PI3K/AKT, impacting vascular remodeling and responsiveness. AKT phosphorylates FOXO, leading to its exclusion from the nucleus and inhibition of its activity. NOTCH dysregulation could impair AKT signaling, potentially resulting in enhanced FOXO activity, which may increase apoptosis under diabetic stress conditions [66]. FOXO factors are crucial for upregulating the expression of genes involved in oxidative stress defense. Dysregulated NOTCH could affect this pathway, diminishing the ability of endothelial cells to cope with oxidative stress, thereby exacerbating endothelial dysfunction. In VSMCs, FOXO transcription factors can influence cell cycle progression and apoptosis. NOTCH-induced disruptions in FOXO activity could lead to increased VSMC proliferation and reduced apoptosis, promoting atherosclerotic lesion development and plaque progression. FOXO factors also play roles in glucose metabolism within VSMCs. Altered NOTCH signaling may disrupt normal FOXO-mediated metabolic processes, contributing to further metabolic dysfunction in diabetic vascular tissues [67]. Combining therapies that target both NOTCH and elements of the insulin signaling pathways (such as PI3K/AKT/mTOR inhibitors) might provide a more comprehensive approach to correcting the underlying molecular dysfunctions. Specifically targeting NOTCH signaling components that interact with insulin signaling pathways may help restore normal cellular functions in vascular tissues. Strategies aimed at modulating FOXO activity could help maintain cellular homeostasis and protect against oxidative stress, potentially mitigating some of the vascular complications of diabetes. Further research into the cross-talk between NOTCH and insulin signaling pathways in the context of diabetes will be crucial for developing targeted interventions that address both the causes and consequences of vascular complications in diabetic patients [68].
Diabetes-Induced Damage Disrupting Homeostasis in Vascular Cells:
NOTCH signaling is crucial for the regulation of numerous vascular functions, including differentiation, proliferation, apoptosis, and response to environmental stimuli [69]. Disruption in NOTCH signaling due to diabetes can therefore lead to multiple vascular pathologies, altering cell fate and function, which can exacerbate the complications associated with diabetes. In endothelial cells, NOTCH plays a key role in the formation of new blood vessels and the maintenance of existing ones. Disruption in NOTCH signaling due to diabetes can lead to ineffective angiogenesis, which is critical for wound healing and tissue repair. Poor angiogenesis contributes to chronic diabetic wounds and poor recovery from vascular injuries. NOTCH signaling also helps maintain endothelial barrier integrity. Dysregulation can increase vascular permeability, leading to enhanced leakage of plasma proteins and infiltration of inflammatory cells, exacerbating vascular inflammation and edema [70]. Moreover, NOTCH influences the expression of genes involved in vascular tone regulation, such as those encoding for smooth muscle contractility proteins. Dysfunctional NOTCH signaling in endothelial cells can lead to dysregulated vasodilation and vasoconstriction, contributing to hypertension, a common complication in diabetes. In vascular smooth muscle cells, NOTCH signaling helps regulate the phenotypic state of VSMCs. In diabetes, abnormal NOTCH signaling can promote a shift from a contractile to a synthetic phenotype, characterized by increased cell proliferation, migration, and extracellular matrix production. This contributes to vascular stiffness and atherosclerotic plaque development. NOTCH signaling in VSMCs also plays a role in the response to lipid accumulation and inflammatory processes within the vessel wall. Dysregulation can accelerate the progression of atherosclerosis, leading to increased cardiovascular risk. Given the role of NOTCH signaling in maintaining vascular cell homeostasis, targeting this pathway could offer potential therapeutic benefits for managing diabetes-induced vascular complications [71]. Pharmacological agents that selectively inhibit or modulate NOTCH signaling could be used to restore normal vascular function and prevent pathological remodeling. Strategies that target NOTCH ligands or their interactions with NOTCH receptors may help fine-tune the signaling outcomes, particularly in the context of angiogenesis and endothelial function. Combining NOTCH pathway modulators with current therapies aimed at controlling glucose levels, reducing oxidative stress, and managing inflammation could provide a more comprehensive approach to treating diabetes-related vascular complications [72]. Advanced therapies that involve gene editing or gene silencing techniques could be developed to specifically target aberrant genes within the NOTCH pathway, thus correcting dysfunctional signaling directly at the source [73].

5. AP-1 (Activator Protein-1)

Diabetes-Induced Disruption of Vascular Cell Fate:
Activator Protein-1 (AP-1) is a transcription factor that plays a crucial role in regulating gene expression in response to a variety of physiological and pathological stimuli, including growth factors, stress, and cytokines. Composed of dimers formed by the Jun, Fos, ATF, and MAF protein families, AP-1 controls essential processes such as differentiation, proliferation, and apoptosis, which are vital for vascular development and maintenance. In diabetes, persistent hyperglycemia, oxidative stress, and inflammatory cytokines can significantly alter the regulation and activity of AP-1 [74]. Chronic high glucose levels lead to increased production of reactive oxygen species (ROS), which can activate AP-1. Excessive AP-1 activity may result in the upregulation of genes involved in oxidative stress and inflammation, perpetuating vascular damage. Moreover, AP-1 is a key mediator of inflammatory responses; hyperglycemia-induced AP-1 activation can enhance the expression of pro-inflammatory cytokines, chemokines, and adhesion molecules, contributing to a pro-inflammatory environment in the vascular system. In vascular endothelial cells (VECs), AP-1 influences the expression of endothelial nitric oxide synthase (eNOS) and other factors important for maintaining endothelial function [75]. Dysregulated AP-1 activity can decrease nitric oxide (NO) production, leading to impaired vasodilation, increased platelet aggregation, and adhesion molecule expression, which contribute to atherosclerosis. AP-1 also plays a role in the regulation of angiogenesis by modulating the expression of various angiogenic factors, including VEGF [76]. Dysregulated AP-1 activity in diabetes can lead to impaired or excessive angiogenesis, affecting wound healing and contributing to diabetic complications such as retinopathy. In vascular smooth muscle cells (VSMCs), AP-1 controls the expression of multiple genes involved in cell proliferation, migration, and the synthesis of extracellular matrix components. Diabetes-induced alterations in AP-1 activity can promote a phenotypic switch in VSMCs from a contractile to a synthetic state, contributing to vascular stiffness and atherosclerotic plaque development. AP-1 promotes the expression of inflammatory mediators and matrix metalloproteinases (MMPs) in VSMCs, which can degrade the extracellular matrix and destabilize atherosclerotic plaques, leading to plaque rupture and acute vascular events. Given the significant role of AP-1 in the pathophysiology of diabetic vascular complications, targeting this transcription factor offers potential therapeutic benefits. Small molecule inhibitors targeting AP-1 components could modulate its transcriptional activity, potentially reducing inflammation and oxidative stress in vascular cells [77]. Since oxidative stress can activate AP-1, antioxidants might reduce its activation indirectly, alleviating vascular inflammation and endothelial dysfunction. Drugs that reduce inflammatory signaling could also diminish AP-1 activity, providing another avenue to mitigate its pathological effects in diabetes [78].
Damage to Downstream Regulators of the Insulin Receptor (PI3K, AKT, mTOR, and FOXO) in Vascular Cells:
Diabetes-induced damage to AP-1 (Activator Protein-1) can profoundly influence the downstream signaling pathways of the insulin receptor, notably PI3K, AKT, mTOR, and FOXO, in vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) [79]. Since AP-1 is a critical mediator of cellular stress responses, including inflammation and oxidative stress, its dysregulation can lead to altered insulin signaling, affecting vascular health and function. In vascular endothelial cells, AP-1 influences the transcription of several inflammatory and pro-atherogenic genes. Overactive AP-1 in diabetes can exacerbate the inflammatory state in endothelial cells, which negatively impacts PI3K/AKT signaling [80]. This disruption can decrease the production of nitric oxide (NO) by affecting endothelial nitric oxide synthase (eNOS), leading to impaired vasodilation and increased vascular tone. Additionally, dysregulated AP-1 due to diabetes can impair the PI3K/AKT pathway's role in promoting cell survival and angiogenesis. For example, disrupted AKT signaling can lead to reduced activation of critical angiogenic factors like VEGF, hindering proper angiogenic responses necessary for vascular repair and maintenance. In vascular smooth muscle cells (VSMCs), diabetes-induced activation of AP-1 may contribute to the synthetic phenotype transformation, characterized by increased proliferation and migration [81]. This transformation is often mediated by the altered activity of the PI3K/AKT pathway, contributing to atherosclerotic plaque formation and vascular stiffening. FOXO transcription factors, key regulators of oxidative stress response and apoptosis in endothelial cells, can also be affected. Dysregulation of AP-1 in diabetes can indirectly lead to altered AKT activity, which typically phosphorylates and inhibits FOXO factors, thus potentially leading to increased oxidative stress and apoptotic processes in endothelial cells. In VSMCs, FOXO factors regulate various genes involved in metabolism and apoptosis [82]. Dysfunctional AKT signaling, influenced by aberrant AP-1 activity, may result in inappropriate activation of FOXO, promoting metabolic disturbances and increased susceptibility to apoptosis, which can exacerbate vascular complications in diabetes. Given the influence of diabetes-induced AP-1 dysregulation on these critical insulin signaling pathways, several therapeutic strategies could be considered. Pharmacological agents that specifically modulate AP-1 activity could help restore normal function to the PI3K/AKT/mTOR and FOXO pathways, improving vascular health. Interventions aimed at enhancing insulin receptor signaling, particularly through modulation of PI3K/AKT, could counteract some of the detrimental effects induced by AP-1 dysregulation. Additionally, antioxidants and anti-inflammatory agents could mitigate the oxidative stress and inflammation that activate AP-1, thereby indirectly improving insulin signaling and overall vascular function [83].
Diabetes-Induced Damage Disrupting Homeostasis in Vascular Cells:
Diabetes-induced damage to Activator Protein-1 (AP-1), a transcription factor complex that plays a critical role in regulating gene expression in response to various physiological and pathological stimuli, can significantly disrupt the homeostasis of vascular cells. The dysregulation of AP-1 in diabetes mainly results from chronic hyperglycemia, oxidative stress, and inflammation, which are prevalent in diabetic conditions. AP-1 is known to regulate the expression of numerous inflammatory genes, including cytokines, chemokines, and adhesion molecules. In diabetes, overactivation of AP-1 can lead to increased expression of these pro-inflammatory mediators, promoting endothelial activation and leukocyte recruitment [84]. This exacerbates vascular inflammation, contributing to endothelial damage and dysfunction. AP-1 influences the regulation of angiogenic factors such as VEGF. Dysfunctional AP-1 activity in diabetes can disrupt normal angiogenic processes, leading to inadequate or abnormal new vessel formation, which is crucial for tissue repair and regeneration. This is particularly detrimental in wound healing and the progression of diabetic retinopathy. AP-1 plays a role in modulating the phenotype of vascular smooth muscle cells (VSMCs). Diabetes-induced activation of AP-1 can drive VSMCs toward a synthetic phenotype, characterized by increased proliferation, migration, and secretion of extracellular matrix proteins. These changes are key in vascular remodeling and contribute to the development and progression of atherosclerosis. In VSMCs, AP-1 regulates the expression of matrix metalloproteinases (MMPs), which can degrade the extracellular matrix. In diabetes, heightened AP-1 activity may increase MMP expression, leading to the destabilization of atherosclerotic plaques, increasing the risk of plaque rupture and subsequent vascular events. Additionally, AP-1 regulates genes involved in maintaining the integrity of the endothelial barrier [85]. Diabetes-induced dysregulation of AP-1 can lead to alterations in tight junction proteins and other components of the endothelial barrier, increasing vascular permeability. This can result in edema and further facilitate the infiltration of inflammatory cells into the vessel wall. AP-1 can also activate the expression of enzymes involved in oxidative stress. In diabetes, persistent high glucose and resultant oxidative stress can overactivate AP-1, leading to further production of reactive oxygen species (ROS) and exacerbating vascular oxidative damage. This creates a vicious cycle of inflammation and oxidative stress that progressively impairs vascular function. Given the significant impact of AP-1 on vascular dysfunction in diabetes, targeting AP-1 or its downstream effects could offer potential therapeutic benefits [86]. Drugs that can specifically inhibit AP-1 activity might reduce inflammation and oxidative stress, thereby improving vascular function and reducing complications. Using antioxidants to reduce ROS levels may indirectly modulate AP-1 activity, mitigating its activation and the subsequent expression of damaging enzymes and cytokines. Reducing systemic inflammation can decrease AP-1 activation, helping to maintain vascular homeostasis and prevent further damage [87].

6. ETS Family Transcription Factors
Diabetes-Induced Disruption of Vascular Cell Fate:
The ETS family of transcription factors, which includes numerous members such as ETS1, ETS2, FLI1, and others, plays a crucial role in the regulation of various genes involved in angiogenesis, inflammation, and the cellular response to mechanical stress [88]. These transcription factors are particularly important in vascular development and maintenance, influencing the behavior of both vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). Diabetes can induce dysregulations in ETS family transcription factors through several mechanisms. Chronic high glucose levels can alter the expression and activity of ETS transcription factors, potentially resulting in changes to their binding affinities or alterations in the expression of their target genes. Increased oxidative stress, a common feature of diabetes, can modify the activity of ETS factors, potentially leading to altered gene expression profiles that affect cell function and survival [89]. Additionally, the pro-inflammatory environment associated with diabetes can influence the regulation and function of ETS factors, impacting their role in inflammatory gene expression. In vascular endothelial cells, ETS factors, particularly ETS1, are involved in the regulation of endothelial nitric oxide synthase (eNOS), which is critical for maintaining endothelial function and vascular tone. Dysregulation of ETS factors in diabetes can lead to decreased NO production, contributing to endothelial dysfunction and increased vascular permeability. ETS factors are key regulators of genes involved in angiogenesis, such as VEGF and angiopoietins. Diabetes-induced alterations in ETS activity can impair the angiogenic response required for normal vascular repair and maintenance, potentially leading to poor wound healing and the progression of diabetic complications such as retinopathy [90]. In vascular smooth muscle cells, ETS factors regulate the expression of genes involved in VSMC proliferation and migration, crucial for vascular remodeling and response to vascular injury. Dysregulated ETS activity in diabetes can promote excessive or inappropriate remodeling, contributing to pathological conditions such as atherosclerosis and restenosis. ETS transcription factors also play a role in maintaining the contractile phenotype of VSMCs. In diabetes, altered ETS signaling can induce a switch to a synthetic phenotype, characterized by increased matrix production and reduced contractility, exacerbating vascular stiffness and dysfunction. Given the key role of ETS family transcription factors in vascular health, targeting these factors or their downstream pathways offers potential therapeutic avenues for the treatment of diabetes-related vascular complications. Developing drugs that specifically modulate the activity of ETS factors could help normalize their function and mitigate adverse effects on vascular cells [91]. Since oxidative stress and inflammation can alter ETS factor activity, using antioxidants and anti-inflammatory drugs could indirectly stabilize ETS function, thereby improving vascular health. Techniques that directly alter the expression or function of specific ETS factors could be explored to correct dysfunctional signaling pathways at a genetic level, offering a targeted approach to treat vascular abnormalities in diabetic patients [92].
Damage to Downstream Regulators of the Insulin Receptor (PI3K, AKT, mTOR, and FOXO) in Vascular Cells:
Diabetes-induced damage to ETS family transcription factors can significantly affect downstream signaling pathways of the insulin receptor, particularly the PI3K/AKT/mTOR and FOXO pathways. These pathways are crucial for maintaining vascular homeostasis, regulating cellular growth, metabolism, and survival. Disruption in ETS function due to diabetes can lead to various vascular dysfunctions in both vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) [93]. In vascular endothelial cells, ETS factors directly influence the expression of multiple genes that regulate endothelial function, including those involved in the synthesis of nitric oxide (NO) via endothelial nitric oxide synthase (eNOS). Dysregulated ETS activity can impair PI3K/AKT signaling, which is critical for eNOS activation. Reduced eNOS activity diminishes NO production, leading to impaired endothelial-dependent vasodilation and contributing to the development of atherosclerosis. ETS factors also regulate angiogenesis by controlling the expression of VEGF and other angiogenic mediators [94]. Disruptions in ETS function may affect PI3K/AKT-mediated responses to these growth factors, impairing normal angiogenic processes essential for tissue repair and regeneration, particularly in diabetic conditions. In vascular smooth muscle cells (VSMCs), ETS factors are key regulators of VSMC behavior, influencing proliferation and migration through PI3K/AKT signaling. Dysregulation due to diabetes can lead to abnormal VSMC activity, promoting inappropriate vascular remodeling and contributing to the pathogenesis of atherosclerosis and vascular stiffness. Additionally, in endothelial cells, FOXO transcription factors are critical for regulating apoptosis and oxidative stress responses [95]. Dysfunctional ETS signaling can disrupt PI3K/AKT pathways, leading to altered FOXO activity. In diabetes, this might result in decreased cell survival and increased susceptibility to oxidative stress, exacerbating vascular damage. ETS factors may also impact the expression of metabolic genes indirectly through effects on FOXO transcription factors. Altered FOXO activity due to disrupted ETS signaling could lead to further metabolic imbalances in endothelial cells, compounding issues like hyperglycemia and lipid abnormalities. FOXO factors in VSMCs regulate several aspects of cell metabolism and phenotype. Diabetes-induced changes in ETS activity could influence PI3K/AKT signaling, impacting FOXO activity and promoting a shift towards a synthetic phenotype which is less contractile and more proliferative, contributing to atherosclerotic changes. The interaction between diabetes-induced alterations in ETS transcription factors and insulin receptor downstream signaling pathways highlights potential therapeutic targets. Therapeutic strategies that aim to correct or modulate ETS factor activity can help restore normal function to the PI3K/AKT/mTOR and FOXO pathways, improving vascular function and reducing diabetic complications [96]. Drugs designed to specifically target these pathways can be used in conjunction to modulate the effects of disrupted ETS signaling, offering a comprehensive approach to treat vascular dysfunction in diabetes. Since oxidative stress and inflammation can exacerbate the dysfunction of ETS factors, using antioxidants and anti-inflammatory agents could help mitigate these effects, indirectly stabilizing the signaling pathways affected [97, 98].
Diabetes-Induced Damage Disrupting Homeostasis in Vascular Cells:
Diabetes-induced damage to ETS family transcription factors can have profound implications for the homeostasis of vascular cells, primarily affecting vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). The ETS family, known for its broad roles in gene expression related to cell cycle regulation, angiogenesis, and inflammatory responses, is crucial in maintaining vascular health and function [99]. Dysregulation of these transcription factors in diabetes can lead to a cascade of vascular issues that contribute to the common complications of diabetes, such as atherosclerosis, retinopathy, nephropathy, and peripheral vascular disease. ETS factors like ETS1 are involved in the regulation of endothelial nitric oxide synthase (eNOS), which is critical for nitric oxide (NO) production. Dysregulation can lead to decreased NO availability, which impairs vasodilation and contributes to endothelial dysfunction, a precursor to atherosclerosis [100]. Additionally, ETS factors regulate the expression of various adhesion molecules and cytokines. Diabetes-induced alterations can enhance the expression of VCAM-1, ICAM-1, and selectins, facilitating the adhesion of leukocytes to endothelial cells and promoting vascular inflammation. Furthermore, ETS transcription factors control the expression of vascular endothelial growth factor (VEGF) and other pro-angiogenic factors. Their dysregulation in diabetes can lead to inappropriate angiogenic responses, which are particularly detrimental in diabetic retinopathy and wound healing processes. In vascular smooth muscle cells (VSMCs), ETS factors are involved in maintaining the contractile phenotype. Diabetes can induce a shift towards a synthetic phenotype, characterized by increased proliferation, migration, and matrix production. This contributes to intimal thickening, vascular stiffening, and the progression of atherosclerosis [101]. Additionally, ETS factors like ETS1 promote the expression of inflammatory cytokines within VSMCs, exacerbating local inflammation and further driving atherosclerotic processes. Given the central role of ETS transcription factors in vascular pathophysiology, targeting these factors offers potential therapeutic avenues. Specific inhibitors targeting ETS transcription factor activation or blocking their binding to DNA could help in correcting their diabetes-induced dysregulation, potentially mitigating vascular complications. Since ETS factors often enhance pro-inflammatory pathways, targeting these pathways with anti-inflammatory drugs could reduce the overall inflammatory burden in the vasculature. Advanced approaches like gene therapy could be used to modulate the expression of specific ETS factors, restoring their normal function and improving vascular health [102].

7. FOXC Transcription Factors
Diabetes-Induced Disruption of Vascular Cell Fate:
FOXC transcription factors, particularly FOXC1 and FOXC2, play critical roles in the regulation of vascular development and homeostasis. These factors are essential for the differentiation and function of vascular cells, including vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). They are involved in various processes such as angiogenesis, barrier integrity, and vascular remodeling [103]. Diabetes can induce dysregulations in FOXC transcription factors through several mechanisms. Prolonged high blood glucose levels can lead to the glycation of proteins and affect the transcriptional activity of many factors, including FOXC. This can alter their ability to bind DNA and regulate gene expression effectively. Increased oxidative stress, a common feature in diabetes, can modify transcription factors and their regulatory proteins, potentially disrupting the normal function of FOXC factors. Additionally, the chronic inflammatory state associated with diabetes can influence the expression and activity of FOXC transcription factors, potentially skewing their normal regulatory functions. In vascular endothelial cells (VECs), FOXC transcription factors regulate genes involved in maintaining endothelial barrier integrity and function [104]. Dysregulation caused by diabetes could lead to impaired barrier function, increased vascular permeability, and subsequent tissue edema and inflammation, contributing to the progression of vascular complications. FOXC factors are crucial in regulating angiogenic signaling pathways. Alterations in their activity due to diabetes might impair normal angiogenesis, affecting wound healing and contributing to the pathological angiogenesis observed in diabetic retinopathy. In vascular smooth muscle cells (VSMCs), FOXC transcription factors influence the phenotypic modulation of VSMCs. Dysregulation in diabetes may promote a shift towards a synthetic phenotype, which is more proliferative and less contractile [105]. This shift contributes to vascular stiffness, increased susceptibility to atherosclerosis, and impaired vascular reactivity. Changes in FOXC function can alter the expression of inflammatory mediators in VSMCs, exacerbating vascular inflammation and further promoting atherosclerotic changes. Given the significance of FOXC transcription factors in maintaining vascular cell function, strategies aimed at correcting their dysregulation in diabetes may offer therapeutic benefits. Targeting glycation and oxidative stress with antioxidant therapy and glycation inhibitors could help maintain the normal function of FOXC transcription factors by reducing oxidative stress and non-enzymatic glycation [106]. Techniques to enhance or restore the expression of FOXC transcription factors could directly address the underlying disruptions caused by diabetes, potentially restoring normal vascular function and improving outcomes. Since inflammation can affect the activity of FOXC transcription factors, anti-inflammatory treatments could indirectly stabilize their function, reducing vascular complications. In conclusion, diabetes-induced dysregulation of FOXC transcription factors significantly impacts the fate and function of vascular cells, contributing to various vascular diseases associated with diabetes [107].
Damage to Downstream Regulators of the Insulin Receptor (PI3K, AKT, mTOR, and FOXO) in Vascular Cells:
Diabetes-induced damage to FOXC transcription factors can significantly impact the regulation of key signaling pathways downstream of the insulin receptor, particularly affecting PI3K, AKT, mTOR, and FOXO pathways. These pathways are central to cellular metabolism, growth, survival, and vascular function. In vascular endothelial cells (VECs), FOXC factors influence the transcription of various genes involved in endothelial cell function, including those regulating angiogenesis and barrier integrity [108]. Dysregulation can impair the PI3K/AKT pathway, critical for endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production, leading to reduced vasodilation and increased vascular tone. FOXC transcription factors also help regulate VEGF expression and other angiogenic factors that signal through the PI3K/AKT pathway. Impaired FOXC activity can disrupt normal angiogenic responses, which are crucial for healing and tissue regeneration, particularly in diabetic conditions where wound healing is compromised. In vascular smooth muscle cells (VSMCs), FOXC factors are involved in regulating the phenotype of VSMCs. Alterations in FOXC activity could impact PI3K/AKT signaling, promoting a shift towards a synthetic phenotype characterized by increased proliferation and migration [109]. This contributes to pathological vascular remodeling, atherosclerosis, and arterial stiffness. FOXC factors also affect FOXO transcription factors which are key in regulating responses to oxidative stress and apoptosis. Dysregulated FOXC factors could lead to impaired activation of the PI3K/AKT pathway, resulting in increased FOXO activity. This might increase susceptibility to oxidative stress and apoptosis in endothelial cells, exacerbating diabetic vascular complications. Impaired FOXC function can influence the regulation of metabolic processes through effects on FOXO transcription factors, which are crucial for maintaining cellular homeostasis and responding to metabolic stress. In VSMCs, FOXO transcription factors regulate genes involved in apoptosis, proliferation, and inflammation [110]. Dysregulation of FOXC transcription factors, impacting PI3K/AKT/FOXO signaling, could contribute to increased cell proliferation, reduced apoptosis, and enhanced inflammation within the vascular wall, promoting atherosclerosis. Given the role of FOXC transcription factors in modulating these insulin receptor downstream pathways, therapeutic strategies could include developing drugs or gene therapies that specifically enhance or inhibit FOXC function to help correct the dysregulated pathways in diabetic vascular cells. Using specific inhibitors or activators of the PI3K/AKT/mTOR pathway could help counteract the negative effects of FOXC dysregulation [111]. Since oxidative stress can further impair FOXC function and subsequent downstream signaling, antioxidants could mitigate these effects and help restore normal cellular functions. Research into how diabetes specifically alters FOXC transcription factors and their impact on downstream insulin signaling pathways could lead to targeted interventions that address the root causes of vascular dysfunction in diabetes, improving outcomes for patients with this condition [112].
Diabetes-Induced Damage Disrupting Homeostasis in Vascular Cells:
Diabetes-induced damage to FOXC transcription factors can significantly disrupt the homeostasis of vascular cells, particularly impacting vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). FOXC transcription factors, including FOXC1 and FOXC2, are crucial in regulating various aspects of vascular development, angiogenesis, and integrity [113]. Their dysregulation due to diabetes can lead to several pathological changes in the vascular system. In vascular endothelial cells, FOXC transcription factors are important in maintaining endothelial barrier integrity. Diabetes-induced alterations can lead to increased vascular permeability, contributing to edema and facilitating the infiltration of inflammatory cells into the vessel wall, which can exacerbate vascular damage. Additionally, FOXC factors influence the expression of endothelial nitric oxide synthase (eNOS). Dysregulation can impair nitric oxide (NO) production, leading to decreased vasodilation and increased susceptibility to vascular inflammation and atherosclerosis [114]. FOXC factors also play roles in the regulation of angiogenic factors such as VEGF. Disruption in their function due to diabetes can lead to abnormal angiogenesis, affecting wound healing and contributing to complications like diabetic retinopathy, where inappropriate new vessel formation can lead to vision loss. In vascular smooth muscle cells (VSMCs), FOXC transcription factors help maintain the contractile phenotype. Their dysregulation in diabetes may induce a shift to a synthetic phenotype, characterized by increased proliferation, migration, and extracellular matrix production. This contributes to vascular remodeling, stiffness, and the progression of atherosclerosis. Changes in FOXC function can also enhance the expression of pro-inflammatory cytokines in VSMCs, promoting an inflammatory environment that accelerates atherosclerotic processes. The combined effects of endothelial dysfunction, increased vascular permeability, and VSMC phenotypic switching contribute to the development and progression of atherosclerotic plaques [115]. Plaque instability, which can result from these processes, increases the risk of serious cardiovascular events such as myocardial infarction and stroke. Impaired endothelial function and vascular stiffness, outcomes of FOXC dysregulation, are significant contributors to the development of hypertension, a common comorbidity in diabetic patients. Given the crucial role of FOXC transcription factors in vascular function, targeting their regulation presents a viable therapeutic approach. Techniques to correct or enhance the expression of specific FOXC genes could directly address functional impairments in vascular cells [116]. Developing drugs that can modulate FOXC transcription factor activity might help restore their normal regulatory functions, mitigating vascular complications. Using anti-inflammatory drugs, antioxidants, and agents that enhance endothelial function in combination with therapies targeting FOXC dysregulation could provide a comprehensive treatment approach [117].

8. GATA Transcription Factors

Diabetes-Induced Disruption of Vascular Cell Fate:
GATA transcription factors, notably GATA2 and GATA4, play vital roles in vascular biology, influencing the differentiation and function of vascular cells, including vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). GATA factors are critical in regulating gene expression associated with cell growth, differentiation, and response to environmental cues [118]. Diabetes can induce dysregulations in GATA transcription factors through several interrelated mechanisms: Chronic high glucose levels can alter the expression and activity of GATA factors, affecting their ability to bind to DNA and regulate target genes effectively. Increased oxidative stress, a hallmark of diabetes, can modify transcription factors directly or disrupt their signaling pathways, potentially altering the function of GATA factors. The inflammatory milieu associated with diabetes can modulate the expression and activity of GATA transcription factors, influencing their role in inflammatory and immune responses within vascular tissues. In vascular endothelial cells, GATA factors, especially GATA2, are involved in regulating endothelial cell integrity and function. Dysregulation caused by diabetes can lead to impaired expression of endothelial genes critical for barrier function and nitric oxide (NO) production, contributing to endothelial dysfunction and increased vascular permeability [119]. GATA transcription factors also regulate genes important for angiogenesis, including VEGF. Impaired function of GATA factors in diabetes can disrupt normal angiogenic responses, which are crucial for healing and tissue repair, particularly affecting wound healing processes in diabetic patients. In vascular smooth muscle cells, GATA factors influence the phenotypic state. Altered GATA function can induce a shift towards a synthetic phenotype, characterized by increased proliferation and migration [120]. This contributes to pathological vascular remodeling, atherosclerosis, and arterial stiffness. Dysregulation of GATA factors can also enhance the expression of inflammatory mediators in VSMCs, exacerbating local inflammation and promoting the development of atherosclerotic plaques. The combined effects of endothelial dysfunction, improper angiogenesis, and phenotypic transformation of VSMCs foster the development and progression of atherosclerosis, significantly increasing the risk of cardiovascular diseases. Impaired endothelial function and vascular remodeling contribute to increased vascular stiffness and resistance, leading to hypertension, a common complication in diabetic patients. Given the crucial role of GATA transcription factors in vascular function, targeting their regulation presents a promising therapeutic approach. Techniques to correct or enhance the expression of specific GATA genes could directly address the root causes of vascular dysfunction in diabetes [121]. Developing drugs that can specifically modulate GATA transcription factor activity might help restore their normal regulatory functions, mitigating vascular complications. Since inflammation and oxidative stress can exacerbate the dysfunction of GATA factors, using anti-inflammatory drugs and antioxidants could help stabilize their function and improve overall vascular health [122].
Damage to Downstream Regulators of the Insulin Receptor (PI3K, AKT, mTOR, and FOXO) in Vascular Cells:
Diabetes-induced damage to GATA transcription factors can significantly influence the downstream signaling pathways related to the insulin receptor, specifically PI3K, AKT, mTOR, and FOXO pathways. These pathways are essential for cellular growth, survival, metabolism, and vascular function [123]. Given that GATA transcription factors are involved in the regulation of vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs), their dysregulation can lead to widespread vascular dysfunction. GATA transcription factors, particularly GATA2, influence the expression of endothelial nitric oxide synthase (eNOS), a key enzyme regulated by the PI3K/AKT pathway that is crucial for nitric oxide (NO) production. Dysregulation of GATA factors can impair PI3K/AKT signaling, resulting in decreased NO production, which contributes to endothelial dysfunction and reduced vascular reactivity. GATA factors are also involved in the regulation of angiogenic factors such as VEGF, which are mediated through the PI3K/AKT pathway [124]. Dysfunctional GATA activity due to diabetes may affect this pathway, leading to impaired angiogenic responses essential for vascular repair and maintenance, particularly impacting wound healing in diabetic conditions. In vascular smooth muscle cells (VSMCs), GATA factors help regulate the balance between contractile and synthetic phenotypes. Altered GATA function in diabetes can disrupt PI3K/AKT signaling, promoting a synthetic phenotype that is characterized by increased proliferation and migration. This phenotypic shift contributes to vascular stiffness, remodeling, and the progression of atherosclerosis. FOXO transcription factors are critical regulators of cellular responses to oxidative stress and apoptosis [125]. Dysregulated GATA activity can lead to impaired PI3K/AKT signaling, resulting in abnormal activation of FOXO factors. This can increase cellular susceptibility to oxidative damage and apoptosis, exacerbating vascular damage in diabetes. GATA factors indirectly influence metabolic processes through effects on FOXO factors, which play a key role in glucose metabolism. Impaired regulation of FOXO due to disrupted GATA function can lead to further metabolic dysregulation in endothelial cells [126]. FOXO factors in VSMCs regulate genes involved in inflammation and cell cycle control. Diabetes-induced dysregulation of GATA factors impacting PI3K/AKT/FOXO signaling could contribute to increased inflammatory responses and cell proliferation, promoting atherosclerotic changes and vascular inflammation. Given the role of GATA transcription factors in modulating these critical insulin receptor downstream pathways, therapeutic strategies could include targeting GATA transcription factor activity with specific inhibitors or enhancers to help restore normal function to affected signaling pathways, improving vascular health. Utilizing drugs that specifically target the PI3K/AKT/mTOR pathway could counteract the negative effects of GATA dysregulation. Since oxidative stress and inflammation can exacerbate the dysfunction of GATA factors and subsequent signaling pathways, antioxidants and anti-inflammatory agents could help stabilize these pathways and improve vascular function [127].
Diabetes-Induced Damage Disrupting Homeostasis in Vascular Cells:
Diabetes-induced damage to GATA transcription factors can have significant implications for the homeostasis of vascular cells, specifically affecting both vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). GATA transcription factors, particularly GATA2 and GATA4, are integral to the regulation of gene expression associated with cell differentiation, growth, and response to environmental stimuli in vascular tissues [128]. Their dysregulation due to diabetes-related factors such as hyperglycemia, oxidative stress, and chronic inflammation can disrupt normal vascular function and contribute to the development of various vascular complications. GATA factors regulate the expression of endothelial nitric oxide synthase (eNOS), which is critical for the production of nitric oxide (NO), a major vasodilator and anti-inflammatory molecule. Dysregulation of GATA factors can lead to reduced NO levels, resulting in impaired vasodilation, increased vascular tone, and endothelial dysfunction. Furthermore, GATA transcription factors also regulate genes involved in inflammatory processes [129]. Dysfunctional GATA activity can increase the expression of pro-inflammatory cytokines and adhesion molecules, enhancing endothelial activation and promoting leukocyte adhesion, which contribute to chronic vascular inflammation. GATA factors are crucial for the expression of angiogenic factors like VEGF. Impaired function due to diabetes can disrupt normal angiogenesis, affecting wound healing and the maintenance of vascular integrity. In diabetic patients, this can lead to poor wound healing and exacerbate conditions such as diabetic foot ulcers. In vascular smooth muscle cells (VSMCs), GATA transcription factors help maintain the contractile phenotype [130]. In diabetes, altered GATA signaling can promote a shift towards a synthetic phenotype characterized by increased cell proliferation, migration, and extracellular matrix production. This shift contributes to pathological vascular remodeling, increased stiffness, and susceptibility to atherosclerosis. Dysregulation of GATA factors can increase the production of inflammatory mediators in VSMCs, promoting vascular inflammation and accelerating the progression of atherosclerotic plaque formation. Given the critical role of GATA transcription factors in vascular health, targeting these factors or their downstream effects could provide therapeutic benefits [131]. Techniques to enhance or suppress the expression of specific GATA genes could be explored to address their dysregulation in diabetes, aiming to restore normal vascular function. Since inflammation and oxidative stress can worsen GATA factor dysfunction, using anti-inflammatory and antioxidant treatments might help stabilize their activity, improving overall vascular health [132, 133]. Additionally, developing drugs that specifically target GATA transcription factor activity could directly mitigate their abnormal function in diabetes, potentially reducing vascular complications [134].

9. SMAD Transcription Factors
Diabetes-Induced Disruption of Vascular Cell Fate:
SMAD transcription factors are central to the signaling pathways of transforming growth factor-beta (TGF-β) and bone morphogenetic proteins (BMPs), both of which play critical roles in vascular development and maintenance. In vascular stem cells, SMAD proteins help mediate responses to these growth factors, influencing cell differentiation, proliferation, migration, and apoptosis [135]. Diabetes-induced dysregulations in SMAD transcription factors can disrupt the cell fate of vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) due to several factors. Chronic high glucose levels can result in the formation of advanced glycation end-products (AGEs), which may interfere with SMAD protein signaling by altering their structure or expression. This interference can distort normal SMAD-mediated cellular responses to environmental cues. Additionally, diabetes significantly increases oxidative stress, which can damage proteins including SMAD transcription factors. This oxidative damage can modify the activation and nuclear translocation of SMAD proteins, impacting their ability to regulate gene expression effectively. Moreover, inflammation associated with diabetes can alter the expression levels and activity of TGF-β and BMPs, subsequently affecting SMAD signaling pathways [136]. Dysregulated cytokine levels may lead to aberrant activation or inhibition of SMAD-dependent transcriptional responses. In vascular endothelial cells, SMAD proteins are involved in regulating endothelial cell health and barrier function. Dysregulation can lead to impaired endothelial cell proliferation and migration, contributing to endothelial dysfunction—a hallmark of diabetic vascular complications. SMAD signaling is crucial for angiogenesis, controlling the expression of various angiogenic factors and their inhibitors [137]. Malfunctioning SMAD signaling in diabetes may lead to inadequate or excessive angiogenic responses, impairing wound healing and contributing to proliferative diabetic complications such as retinopathy. In vascular smooth muscle cells, SMAD proteins regulate the phenotypic switch between contractile and synthetic states. In diabetes, altered SMAD signaling can favor the synthetic phenotype, leading to increased cell proliferation, migration, and extracellular matrix production, contributing to vascular stiffness and atherosclerosis. Additionally, in VSMCs, TGF-β/SMAD signaling is a key pathway leading to fibrosis. Diabetes-induced dysregulation may increase fibrotic responses, contributing to vascular thickening and loss of elasticity, which are characteristic of diabetic microvascular and macrovascular diseases [138]. Given the role of SMAD transcription factors in vascular cell fate, strategies to modulate their activity could offer potential therapeutic benefits. Targeting specific components of the TGF-β/SMAD signaling pathway could help normalize the pathological signaling induced by diabetes. This includes using ligand traps, receptor inhibitors, or selective modulators that can enhance or inhibit SMAD signaling as required. Reducing oxidative stress with antioxidants may help preserve the normal function of SMAD proteins, thus maintaining proper response to TGF-β and BMP signals. Since inflammation can disrupt TGF-β/BMP and SMAD signaling, anti-inflammatory drugs might indirectly stabilize SMAD function and improve vascular health in diabetic patients [139].
Damage to Downstream Regulators of the Insulin Receptor (PI3K, AKT, mTOR, and FOXO) in Vascular Cells:
Diabetes-induced damage to SMAD transcription factors can significantly impact the downstream signaling pathways of the insulin receptor, specifically affecting PI3K, AKT, mTOR, and FOXO. These pathways are central to cellular processes such as metabolism, growth, and survival, which are crucial for the normal functioning of vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) [140]. The interaction between SMAD transcription factors and these insulin signaling pathways is complex and plays a significant role in vascular homeostasis and diabetes-related vascular complications. In vascular endothelial cells, SMAD transcription factors regulate the expression of numerous genes involved in endothelial cell health and vascular integrity. Dysregulation of SMAD factors due to diabetes can alter the response to TGF-β, affecting the PI3K/AKT pathway which is crucial for endothelial nitric oxide synthase (eNOS) activation. Impaired eNOS activity leads to reduced nitric oxide (NO) production, contributing to endothelial dysfunction and increased vascular permeability [141, 142]. The PI3K/AKT pathway also regulates angiogenesis, a process critical for wound healing and tissue repair. Dysfunctional SMAD signaling in diabetes may interfere with the proper activation of PI3K/AKT needed for effective angiogenic responses, thereby impairing wound healing and contributing to chronic diabetic ulcers. In vascular smooth muscle cells (VSMCs), the TGF-β/SMAD signaling pathway influences cellular proliferation and migration, processes that are integral to vascular remodeling. Diabetes-induced alterations in SMAD signaling can disrupt normal PI3K/AKT signaling, leading to abnormal proliferation and migration of VSMCs. This contributes to the pathogenesis of vascular diseases such as atherosclerosis and restenosis [143]. FOXO factors are critical regulators of apoptosis, cell cycle control, and oxidative stress response. Altered SMAD signaling due to diabetes may influence PI3K/AKT activity, leading to deregulated FOXO activity. Enhanced FOXO activity due to impaired AKT signaling can increase apoptosis and oxidative stress, exacerbating endothelial damage and vascular dysfunction. FOXO transcription factors also play roles in metabolic regulation. Dysfunctional SMAD signaling affecting PI3K/AKT pathways could impair the normal inhibition of FOXO by AKT, leading to inappropriate activation of genes involved in gluconeogenesis and other metabolic processes in vascular cells. Similar to VECs, altered SMAD signaling in diabetes can affect the regulation of FOXO factors in VSMCs, potentially leading to increased cellular stress responses, senescence, and a pro-inflammatory state, which contribute to vascular aging and dysfunction. Given the significant role of SMAD transcription factors in modulating insulin signaling pathways, targeted therapeutic strategies could include developing drugs that specifically target the SMAD/TGF-β pathway to help correct the dysfunctional signaling observed in diabetes, potentially restoring normal function to PI3K/AKT/mTOR and FOXO pathways [144]. Drugs that modulate the PI3K/AKT/mTOR pathway can be used to counteract the effects of SMAD dysregulation, helping to maintain cellular function and vascular health. Since oxidative stress and inflammation can exacerbate the dysfunction of SMAD and subsequent signaling pathways, using antioxidants and anti-inflammatory agents might help stabilize these pathways and improve vascular function [145].
Diabetes-Induced Damage Disrupting Homeostasis in Vascular Cells:
Diabetes-induced damage to SMAD transcription factors can significantly disrupt the homeostasis of vascular cells, affecting both vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). SMAD proteins are central mediators in the transforming growth factor-beta (TGF-β) signaling pathway, which is vital for maintaining vascular integrity, promoting cell survival, regulating cell growth, and modulating inflammatory responses. Their dysregulation due to diabetes can lead to a cascade of vascular abnormalities that contribute to the development of various diabetic complications [146]. In vascular endothelial cells, SMAD transcription factors regulate the expression of angiogenic factors such as VEGF. Diabetes-induced alterations in SMAD function can impair angiogenic signaling, leading to defective angiogenesis. This is particularly detrimental in healing wounds and in maintaining vascular integrity, exacerbating issues such as diabetic foot ulcers and retinopathy. Proper SMAD signaling is necessary for maintaining endothelial barrier integrity. Dysfunctional SMAD signaling can lead to increased vascular permeability, which promotes the leakage of plasma proteins and facilitates the infiltration of inflammatory cells into the vessel wall, exacerbating vascular damage and edema. SMAD proteins, particularly when linked with TGF-β signaling, play roles in controlling inflammatory processes. Dysregulated SMAD signaling can skew the balance towards a pro-inflammatory state in endothelial cells, contributing to chronic inflammation observed in diabetic vasculature. In vascular smooth muscle cells, SMAD proteins help regulate the balance between contractile and synthetic phenotypes. Dysregulation of SMAD due to diabetes can favor the synthetic phenotype, characterized by enhanced proliferation, migration, and extracellular matrix production [147]. This contributes to arterial stiffness, intimal hyperplasia, and the progression of atherosclerosis. SMAD signaling is a key mediator of fibrosis. In diabetes, altered SMAD signaling can lead to increased deposition of collagen and other matrix components by VSMCs, further contributing to vascular stiffness and reducing compliance. The combined effects of endothelial dysfunction, improper angiogenesis, and VSMC phenotypic transformation foster the development and progression of atherosclerosis. These conditions significantly increase the risk of cardiovascular diseases, which are major complications of diabetes [148]. Impaired endothelial function and increased vascular stiffness, outcomes of dysfunctional SMAD signaling, are significant contributors to the development of hypertension, a common comorbidity in diabetic patients. Given the crucial role of SMAD transcription factors in vascular health, targeting their regulation presents a viable therapeutic approach. Specific inhibitors or modulators that target the TGF-β/SMAD pathway could help normalize its signaling, potentially mitigating the pathological changes induced by diabetes [149]. Given the role of SMAD in promoting fibrosis, anti-fibrotic therapies could be beneficial in managing diabetes-induced vascular complications. Reducing inflammation and oxidative stress might help stabilize SMAD function and improve overall vascular health [150, 151].

10. Nrf2
Diabetes-Induced Disruption of Vascular Cell Fate:
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor known for its role in cellular defense mechanisms against oxidative stress [152]. Nrf2 regulates the expression of various antioxidant response element (ARE)-driven genes that encode detoxifying enzymes and antioxidant proteins. In vascular stem cells and differentiated vascular cells, including vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs), Nrf2 plays a key role in maintaining cellular redox homeostasis, which is vital for protecting these cells from oxidative damage and dysfunction [153]. In diabetes, hyperglycemia, increased formation of advanced glycation end-products (AGEs), and elevated oxidative stress can lead to dysregulation of Nrf2. Chronic hyperglycemia can lead to a decrease in Nrf2 activity either directly through glycation of the Nrf2 protein or indirectly by modifying Keap1, a repressor protein that binds Nrf2 and promotes its degradation. Impaired Nrf2 activity diminishes the cellular antioxidant response, making cells more susceptible to oxidative damage. Diabetes often results in increased oxidative stress due to the overproduction of reactive oxygen species (ROS) and diminished antioxidant defense [154]. Dysregulated Nrf2 in diabetes can fail to adequately upregulate critical antioxidant genes, leading to cellular damage and exacerbation of diabetic complications. Nrf2 is essential for the antioxidant defense in endothelial cells. Reduced Nrf2 activity can lead to oxidative damage to endothelial cells, impairing nitric oxide (NO) production and contributing to endothelial dysfunction—a hallmark of diabetic vascular disease [155]. This dysfunction is characterized by reduced vasodilation, increased vascular permeability, and enhanced leukocyte adhesion. Nrf2 also modulates inflammatory pathways in endothelial cells [156]. Insufficient Nrf2 activity can lead to elevated expression of pro-inflammatory cytokines and adhesion molecules, promoting inflammation within the vascular wall. In vascular smooth muscle cells (VSMCs), Nrf2 plays a role in modulating the oxidative stress response during vascular remodeling. Dysregulation of Nrf2 in diabetes can lead to increased ROS levels, which promote phenotypic switching of VSMCs from a contractile to a synthetic state [157]. This phenotypic change is associated with increased cell proliferation, migration, and extracellular matrix production, contributing to vascular stiffness and atherosclerosis. Reduced Nrf2 activity exacerbates oxidative stress and inflammation in VSMCs, enhancing the vulnerability of vascular cells to atherosclerotic changes. Oxidative stress can promote the oxidation of lipids, contributing to the formation and progression of atherosclerotic plaques. Given the protective role of Nrf2 in vascular health, enhancing its activity could be a promising therapeutic strategy for managing diabetes-induced vascular complications. Pharmacological activation of Nrf2 using compounds like sulforaphane or bardoxolone methyl can enhance the antioxidant capacity of vascular cells, potentially mitigating oxidative stress and improving vascular function [158]. Supplementing with antioxidants can support the endogenous antioxidant pathways regulated by Nrf2, offering a strategy to reduce oxidative damage in vascular cells. Diet and exercise have been shown to influence Nrf2 activity. Encouraging lifestyle changes that enhance Nrf2 activity could be part of a comprehensive approach to managing diabetes and its vascular complications [159].
Damage to Downstream Regulators of the Insulin Receptor (PI3K, AKT, mTOR, and FOXO) in Vascular Cells:
Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in regulating cellular antioxidant responses, and its activity can significantly influence metabolic pathways, including those downstream of the insulin receptor, such as PI3K, AKT, mTOR, and FOXO. Diabetes-induced damage to Nrf2 may disrupt these pathways, compounding the metabolic and vascular complications associated with diabetes [160]. In vascular endothelial cells (VECs), Nrf2 supports endothelial function by regulating antioxidant defense mechanisms that protect endothelial cells from oxidative stress. When Nrf2 function is compromised in diabetes, increased oxidative damage can inhibit the PI3K/AKT pathway, crucial for endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production. Reduced NO availability leads to impaired vasodilation, increased vascular tone, and endothelial dysfunction. Dysfunctional Nrf2 may lead to decreased activation of PI3K/AKT, failing to suppress pro-inflammatory signaling pathways and increasing vascular permeability [161]. This can exacerbate the leakage of plasma constituents and contribute to inflammation and atherogenesis. In vascular smooth muscle cells (VSMCs), the PI3K/AKT pathway regulates cell proliferation and migration. Reduced Nrf2 activity enhances oxidative stress, which can aberrantly activate the PI3K/AKT pathway, promoting VSMC proliferation and contributing to pathological vascular remodeling and stiffness often observed in diabetes. FOXO transcription factors are crucial for initiating cellular responses to oxidative stress [162]. In diabetes, with impaired Nrf2 function, there is insufficient activation of antioxidant response elements, leading to inadequate regulation of oxidative stress. As a result, AKT-mediated inhibition of FOXO may be compromised, inadequately responding to increased cellular stress and potentially leading to apoptosis or endothelial injury. Dysregulated Nrf2 activity affects FOXO's role in metabolic processes by influencing its regulation through the AKT pathway. Uncontrolled FOXO activity due to disrupted AKT signaling can lead to altered expression of genes involved in glucose metabolism, exacerbating hyperglycemia-related damage. In the context of diabetes, oxidative stress exacerbated by impaired Nrf2 function can lead to dysregulated PI3K/AKT signaling, resulting in increased FOXO activity [163]. This may promote premature senescence and apoptosis of VSMCs, contributing to vascular aging and dysfunction. Increased FOXO activity, due to diminished Nrf2-mediated control, may enhance the transcription of pro-inflammatory genes in VSMCs, promoting vascular inflammation and atherogenesis. The interaction between Nrf2 dysfunction and the downstream insulin signaling pathways suggests potential therapeutic targets: pharmacologically enhancing Nrf2 activity could help restore normal functioning of PI3K/AKT/mTOR and FOXO pathways, reducing oxidative stress and improving vascular health. Using Nrf2 activators in combination with drugs that target PI3K/AKT/mTOR or FOXO pathways could provide a synergistic approach to managing diabetes-induced vascular complications. Boosting antioxidant defenses through dietary or pharmacological means might compensate for the reduced Nrf2 activity and help stabilize downstream insulin signaling pathways, improving overall vascular function and reducing diabetes complications [164].
Diabetes-Induced Damage Disrupting Homeostasis in Vascular Cells:
Diabetes-induced damage to Nuclear factor erythroid 2-related factor 2 (Nrf2) can severely disrupt the homeostasis of vascular cells, leading to significant consequences for vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) [165]. Nrf2 is a critical regulator of cellular antioxidant responses, orchestrating the expression of a host of genes that protect against oxidative stress. In the vascular context, proper Nrf2 function is essential for maintaining the redox balance, which influences everything from endothelial integrity to smooth muscle cell behavior. With compromised Nrf2 activity, endothelial cells suffer from increased oxidative damage due to the diminished expression of antioxidant enzymes such as heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), and glutathione S-transferases [166]. This leads to reduced nitric oxide (NO) availability, impairing vasodilation and increasing susceptibility to atherosclerosis. Nrf2 normally suppresses NF-κB, a key regulator of inflammation. Diabetes-induced Nrf2 dysfunction can result in enhanced NF-κB activity, promoting the expression of inflammatory cytokines and adhesion molecules, thus facilitating leukocyte adhesion and vascular inflammation. Disruption in Nrf2 signaling affects the expression of angiogenic factors and their regulatory proteins, impairing the ability of endothelial cells to form new blood vessels. This is particularly detrimental in diabetic wound healing, where efficient angiogenesis is crucial. In vascular smooth muscle cells (VSMCs), Nrf2 dysfunction can lead to increased oxidative stress, promoting a shift in VSMCs from a contractile to a synthetic phenotype. This phenotype is characterized by enhanced proliferation and migration, as well as increased production of extracellular matrix components, contributing to vascular stiffness and atherosclerosis. Increased oxidative stress in VSMCs, due to inadequate Nrf2 activity, can also accelerate the process of vascular calcification, a common feature in diabetic vascular disease, which further contributes to stiffness and reduced vessel compliance [167]. The combined endothelial dysfunction, increased inflammation, and maladaptive vascular remodeling facilitate the development and progression of atherosclerotic plaques, increasing the risk of cardiovascular events. Impaired endothelial-derived NO production and increased arterial stiffness contribute to the development of hypertension, a common comorbidity in diabetes. Given the key role of Nrf2 in vascular health, targeting its pathway offers potential therapeutic benefits. Compounds that can enhance Nrf2 activation, such as sulforaphane or bardoxolone methyl, might restore antioxidant defense mechanisms, reducing oxidative stress and inflammation in vascular cells. Direct supplementation with antioxidants could help counterbalance the reduced efficacy of endogenous antioxidant systems due to Nrf2 impairment. Dietary changes and exercise have been shown to influence Nrf2 activity; promoting such lifestyle adjustments could enhance Nrf2 activation naturally [168].

11. PAX3/7
Diabetes-Induced Disruption of Vascular Cell Fate:
PAX3 and PAX7 are members of the paired box (PAX) family of transcription factors, which are crucial in early development and play roles in cell lineage determination and differentiation [169]. While PAX3 and PAX7 are prominently known for their roles in muscle and neural development, their influence extends into vascular biology, particularly in the regulation of vascular progenitor cells and their differentiation into vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). In diabetes, several pathophysiological mechanisms could potentially influence the function and regulation of PAX3 and PAX7 transcription factors [170]. Persistent high blood glucose levels can lead to the glycation of proteins, including transcription factors, potentially altering their function. Glycation could affect the DNA-binding ability of PAX3/7, impairing their regulatory roles in gene expression [171]. Increased oxidative stress, a hallmark of diabetes, can damage cellular components, including nucleic acids and proteins. Oxidative modifications might inhibit the function of PAX3/7 or disrupt their normal signaling pathways. Chronic inflammation associated with diabetes might alter the expression or activity of PAX3/7. Inflammatory cytokines could modulate the expression levels of these transcription factors or interfere with their signaling pathways [172]. In vascular endothelial cells, PAX transcription factors are involved in the differentiation and maintenance of endothelial cells. Dysregulated PAX3/7 activity could impair endothelial cell function, reducing their ability to maintain vascular integrity and control vascular tone. This can contribute to endothelial dysfunction, a critical factor in the development of diabetic vascular complications such as atherosclerosis and peripheral artery disease. PAX3/7 also influence the expression of genes critical for angiogenesis [173]. In diabetes, compromised PAX3/7 function might result in inadequate angiogenic responses, which are essential for wound healing and the response to ischemic conditions. The role of PAX3/7 in VSMCs is less clear but likely involves regulation of cellular differentiation and phenotype. Dysregulation in diabetes could lead to abnormal VSMC behavior, contributing to pathological vascular remodeling, increased vascular stiffness, and the progression of atherosclerosis. If diabetes impacts the ability of PAX3/7 to regulate VSMC proliferation and migration properly, it may lead to abnormal vessel formation and stability, affecting overall vascular health and function. Given the potential roles of PAX3 and PAX7 in vascular health and disease, understanding their specific dysregulations in diabetes could open up new therapeutic avenues. Approaches that directly target the genetic regulation of PAX3/7 could help correct their dysfunctional expression or activity in diabetic vascular disease. Since oxidative stress can impair the function of transcription factors like PAX3/7, antioxidant therapy might help preserve their activity and support normal vascular function. Controlling the inflammatory milieu in diabetes might help stabilize PAX3/7 function, reducing their dysregulation and consequent vascular complications. Further research into the specific roles of PAX3 and PAX7 in vascular cell biology, particularly in the context of diabetes, is essential to fully understand their functions and potential as targets for therapeutic intervention. This research could lead to better strategies to mitigate the vascular complications associated with diabetes, improving clinical outcomes for diabetic patients [174].
Damage to Downstream Regulators of the Insulin Receptor (PI3K, AKT, mTOR, and FOXO) in Vascular Cells:
Diabetes-induced damage to PAX3/7 transcription factors can significantly impact the signaling pathways downstream of the insulin receptor, particularly affecting PI3K, AKT, mTOR, and FOXO pathways. These pathways play critical roles in regulating cellular growth, metabolism, survival, and vascular functions in both vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) [175]. Dysregulation of PAX3/7 can lead to impaired activation of the PI3K/AKT pathway, which is crucial for endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production in endothelial cells. This may result in diminished vasodilation, increased vascular tone, and endothelial dysfunction. PAX3/7 factors may also impact the expression of proteins involved in maintaining the endothelial barrier. Impaired PI3K/AKT signaling, resulting from PAX dysregulation, could increase vascular permeability, contributing to edema and the progression of vascular diseases. In vascular smooth muscle cells (VSMCs), altered PAX function might affect the PI3K/AKT pathway, leading to enhanced proliferation and migration. This contributes to vascular remodeling, increased stiffness, and the development of atherosclerosis [176]. Dysregulation of PAX3/7 could lead to inadequate regulation of the PI3K/AKT pathway, resulting in uncontrolled activation or inhibition of FOXO factors. This may increase cellular susceptibility to oxidative damage and apoptosis, exacerbating endothelial damage and vascular dysfunction. Since FOXO factors also play roles in glucose metabolism, the disturbed function of PAX3/7 affecting AKT signaling could lead to metabolic dysregulation in endothelial cells, compounding the metabolic challenges associated with diabetes. In VSMCs, FOXO factors regulate genes involved in inflammation, cell cycle control, and apoptosis. Diabetes-induced dysregulation of PAX3/7 impacting PI3K/AKT/FOXO signaling could promote increased cell proliferation, inflammation, and contribute to the progression of atherosclerotic changes [177]. Given the role of PAX3/7 in modulating these critical insulin receptor downstream pathways, therapeutic strategies could include directly targeting PAX3/7 transcription factor activity with specific inhibitors or enhancers to help normalize their function and restore downstream signaling, improving vascular health. Utilizing drugs that target the PI3K/AKT/mTOR pathway can help counteract the negative effects of PAX dysregulation, maintaining endothelial function and preventing vascular remodeling. Since oxidative stress and inflammation can exacerbate the dysfunction of transcription factors and subsequent signaling pathways, using antioxidants and anti-inflammatory agents might help stabilize these pathways and improve vascular function [178]. Research into the specific interactions between diabetes-induced alterations in PAX3/7 and their impact on insulin signaling pathways will be crucial for developing targeted interventions that effectively address the root causes of vascular dysfunction in diabetes, ultimately improving outcomes for patients with this condition [179].
Diabetes-Induced Damage Disrupting Homeostasis in Vascular Cells:
Diabetes-induced damage to PAX3/7 transcription factors can lead to significant disruptions in the homeostasis of vascular cells, including vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). PAX3 and PAX7 are crucial for development and differentiation, and their dysfunction can affect the fundamental processes of cell growth, differentiation, and survival within the vascular system. Dysfunctional PAX3/7 in diabetes can lead to impaired angiogenic responses, which are crucial for healing wounds and maintaining vascular integrity. This can result in poor wound healing, a common complication in diabetes, and contribute to the progression of diabetic retinopathy [180]. PAX3/7 may also impact the expression of endothelial nitric oxide synthase (eNOS), which is critical for nitric oxide (NO) production. Disruption in their function can lead to decreased NO levels, contributing to vascular stiffness, increased vascular tone, and enhanced susceptibility to atherosclerosis. Dysregulated PAX3/7 can also disrupt endothelial cell function, increasing vascular permeability, which can exacerbate edema and promote the infiltration of inflammatory cells, exacerbating vascular inflammation. In vascular smooth muscle cells (VSMCs), dysregulation caused by diabetes can promote a shift to a synthetic phenotype, characterized by increased cell proliferation, migration, and extracellular matrix production [181]. This phenotypic change contributes to pathological vascular remodeling, increased vascular stiffness, and the progression of atherosclerosis. Dysfunctional PAX3/7 can also lead to increased expression of inflammatory cytokines in VSMCs, promoting an inflammatory environment within the vascular wall, which is a key contributor to the development of atherosclerosis. The combined effects of endothelial dysfunction, improper angiogenesis, and abnormal VSMC behavior foster the development and progression of atherosclerosis, significantly increasing the risk of cardiovascular diseases, which are major complications of diabetes [182]. Impaired endothelial function and increased arterial stiffness, outcomes of dysfunctional PAX3/7 signaling, are significant contributors to the development of hypertension, a common comorbidity in diabetic patients. Given the critical role of PAX3/7 in vascular cell function, targeting their regulation presents a promising therapeutic approach. Techniques to correct or enhance the expression of specific PAX genes could directly address their dysregulation in diabetes, aiming to restore normal vascular function. Since inflammation and oxidative stress can worsen PAX factor dysfunction, using anti-inflammatory drugs and antioxidants might help stabilize their function and improve overall vascular health. Developing drugs that can modulate PAX3/7 activity could help mitigate their abnormal function, reducing vascular complications. Further research into how diabetes specifically alters PAX3/7 function in vascular contexts will provide valuable insights for designing effective treatments to manage diabetic vascular complications, improving clinical outcomes for diabetic patients [183, 184].

12. FOXP1
Diabetes-Induced Disruption of Vascular Cell Fate:
FOXP1 (Forkhead box protein P1) is a member of the forkhead family of transcription factors, known for its roles in regulating gene expression linked to cell growth, differentiation, and longevity [185]. In vascular biology, FOXP1 has emerged as a key player in modulating the function and development of vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). This transcription factor is implicated in several critical processes including endothelial integrity, inflammation response, and smooth muscle cell differentiation. In diabetes, several factors can induce dysregulation of FOXP1, impacting its normal function [186]. Chronic high glucose levels can influence FOXP1 expression and activity, potentially through the production of advanced glycation end-products (AGEs) that interfere with DNA-binding activities or through the modification of signaling pathways that regulate FOXP1 transcription and translation. Increased oxidative stress, a common feature of diabetes, can directly damage proteins including transcription factors like FOXP1. This oxidative modification can alter FOXP1's stability, its localization, or its ability to bind to DNA, thereby affecting its transcriptional activity. The pro-inflammatory environment in diabetes can alter the expression levels of FOXP1 or modulate its activity [187]. Inflammation-driven signaling pathways may enhance or suppress FOXP1 activity, affecting its role in cell regulatory mechanisms. FOXP1 is important for maintaining endothelial barrier function and regulating the inflammatory response. Dysregulated FOXP1 in diabetes can lead to impaired endothelial cell function, characterized by reduced nitric oxide (NO) production, increased endothelial permeability, and enhanced leukocyte adhesion. This dysfunction is a precursor to atherosclerosis and other vascular complications. FOXP1 influences endothelial cell proliferation and tube formation, essential components of angiogenesis. Diabetes-induced alterations in FOXP1 expression or activity may impair angiogenic processes, critical for wound healing and recovery from ischemic events [188]. FOXP1 plays a role in regulating the phenotype of VSMCs. In diabetes, altered FOXP1 expression can contribute to the phenotypic switching of VSMCs from a contractile to a synthetic state, promoting increased cell proliferation, migration, and extracellular matrix production. These changes are central to vascular remodeling, arterial stiffness, and the pathogenesis of hypertension. FOXP1 can regulate the expression of inflammatory genes in VSMCs. Dysregulation in diabetes might lead to heightened inflammatory activity within the vascular wall, contributing to the development of atherosclerosis. Considering the role of FOXP1 in vascular health, strategies to modulate its activity could provide therapeutic benefits. Directly targeting the expression or function of FOXP1 through genetic approaches could normalize its activity in vascular tissues affected by diabetes. Given the impact of oxidative stress on FOXP1 function, antioxidants might stabilize FOXP1 activity, helping to maintain vascular homeostasis. Controlling systemic inflammation could help preserve FOXP1 function, potentially mitigating its dysregulation and the associated vascular complications. Further investigations into how diabetes specifically affects FOXP1 in vascular cells will enhance our understanding of the pathophysiological mechanisms underlying diabetic vascular complications and might lead to novel therapeutic approaches targeting this transcription factor. Such strategies could significantly improve the management and outcomes of diabetic vascular diseases [189].
Damage to Downstream Regulators of the Insulin Receptor (PI3K, AKT, mTOR, and FOXO) in Vascular Cells:
Diabetes-induced damage to FOXP1 (Forkhead box protein P1) could have cascading effects on crucial insulin signaling pathways, specifically impacting the PI3K/AKT/mTOR and FOXO pathways in vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). FOXP1 is integral in maintaining endothelial cell integrity and function [190]. Dysregulation of FOXP1 can impact the PI3K/AKT pathway, which is critical for promoting endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) production. Impaired PI3K/AKT signaling due to FOXP1 dysregulation can lead to reduced NO synthesis, contributing to endothelial dysfunction, a key feature in the development of diabetic vascular disease [191]. Additionally, FOXP1 influences the expression of inflammatory mediators and barrier function proteins through its regulatory roles. If diabetes impairs FOXP1, it may result in abnormal activation of the PI3K/AKT pathway, potentially increasing vascular permeability and exacerbating inflammatory responses in vascular tissues. FOXP1 also helps regulate the balance between the contractile and synthetic phenotypes of VSMCs. Dysregulated FOXP1 in diabetes may alter PI3K/AKT signaling, promoting a shift towards a synthetic phenotype characterized by increased proliferation and migration. Such changes are crucial in the pathogenesis of vascular remodeling and atherosclerosis [192]. In the context of FOXO transcription factors, which are key regulators of cellular responses to oxidative stress and apoptosis, dysregulation of FOXP1 may impair normal PI3K/AKT signaling, which typically inhibits FOXO activity. Altered regulation could lead to enhanced FOXO activity, increasing susceptibility to oxidative stress and apoptosis, thereby exacerbating endothelial cell damage. Since FOXO transcription factors also play significant roles in regulating metabolic processes, impaired regulation by FOXP1 due to diabetes could further disrupt these processes, exacerbating metabolic dysfunction within endothelial cells. In VSMCs, FOXO factors influence inflammation and cellular proliferation. Diabetes-induced FOXP1 dysregulation, leading to abnormal PI3K/AKT signaling, could result in deregulated FOXO activity, potentially enhancing pro-inflammatory gene expression and contributing to the development of atherosclerotic plaques [193]. Given the significant impact of FOXP1 on these critical insulin signaling pathways, potential therapeutic strategies could include drugs that can specifically modulate FOXP1 activity to help correct its dysregulation and restore normal signaling in PI3K/AKT/mTOR and FOXO pathways, improving vascular health. Targeting these pathways directly could also help counteract the effects of FOXP1 dysregulation, stabilizing vascular function in diabetes. Addressing increased oxidative stress and inflammation with antioxidants and anti-inflammatory drugs might mitigate the downstream effects of FOXP1 dysregulation on these pathways. Continued research into the interaction between diabetes-induced FOXP1 dysregulation and downstream insulin signaling pathways will be crucial for developing targeted interventions that can effectively address the root causes of vascular dysfunction in diabetes, potentially leading to better clinical outcomes for patients with this condition [194].
Diabetes-Induced Damage Disrupting Homeostasis in Vascular Cells:
Diabetes-induced damage to FOXP1 (Forkhead box protein P1) can have profound implications on the homeostasis of vascular cells, including vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). FOXP1 plays critical roles in regulating gene expression crucial for cellular growth, differentiation, inflammation, and oxidative stress management. Disruption of FOXP1 function can lead to multiple vascular dysfunctions commonly associated with diabetic complications. In VECs, FOXP1 influences the expression of endothelial nitric oxide synthase (eNOS), which is essential for nitric oxide (NO) production [195]. Dysregulation of FOXP1 in diabetes can lead to decreased NO synthesis, contributing to impaired vasodilation, increased arterial stiffness, and higher susceptibility to atherosclerosis. FOXP1 also helps regulate the expression of inflammatory cytokines and adhesion molecules. Its impairment can enhance endothelial activation, leading to increased adhesion of inflammatory cells to the endothelium, promoting vascular inflammation and the progression of vascular diseases. Additionally, FOXP1 plays a role in the regulation of angiogenic factors. Altered FOXP1 activity due to diabetes may impair normal angiogenesis, affecting wound healing processes and the response to ischemic injury, critical issues in diabetic patients. In VSMCs, FOXP1 is involved in regulating the phenotype [196]. Dysfunctional FOXP1 can lead to a phenotypic switch from a contractile to a synthetic state, characterized by increased proliferation and migration, and enhanced production of extracellular matrix components. This contributes to vascular remodeling, stiffness, and the development of atherosclerosis. Dysregulated FOXP1 may also enhance the expression of inflammatory mediators in VSMCs, exacerbating vascular inflammation and accelerating atherosclerotic processes. The combined effects of endothelial dysfunction, impaired angiogenesis, and abnormal VSMC behavior foster the development and progression of atherosclerosis, significantly increasing the risk of cardiovascular diseases, which are major complications of diabetes. Impaired endothelial-derived NO production and increased arterial stiffness, outcomes of dysfunctional FOXP1 signaling, are significant contributors to the development of hypertension, a common comorbidity in diabetic patients. Given the critical role of FOXP1 in vascular cell function, targeting its regulation presents a promising therapeutic approach [197]. Techniques to correct or enhance the expression of FOXP1 could directly address its dysregulation in diabetes, aiming to restore normal vascular function. Since inflammation and oxidative stress can exacerbate FOXP1 dysfunction, using anti-inflammatory drugs and antioxidants might help stabilize its function and improve overall vascular health. Developing drugs that can modulate FOXP1 activity could help mitigate its abnormal function, reducing vascular complications. Further research into the specific roles of FOXP1 in vascular cell biology, particularly in the context of diabetes, is essential to fully understand their functions and potential as targets for therapeutic intervention. This could lead to better strategies to mitigate the vascular complications associated with diabetes, improving clinical outcomes for diabetic patients [198].

Transcription Factor Dysregulation and Vascular Health: The transcription factors such as Nrf2, FOXP1, PAX3/7, and GATA play key roles in maintaining vascular cell functionality and integrity. In diabetes, the dysfunction of these factors, driven by persistent hyperglycemia and oxidative stress, leads to significant impairments in endothelial function and smooth muscle cell behavior. The findings underscore the crucial impact of transcription factor dysregulation on endothelial nitric oxide synthesis, vascular permeability, and inflammatory responses. The reduced expression and activity of Nrf2, for example, compromise the antioxidant defenses, exacerbating oxidative stress and inflammatory damage within vascular cells.

Implications for Endothelial Dysfunction and Vascular Remodeling: Endothelial dysfunction and vascular remodeling are hallmark features of diabetic vascular disease. The disrupted signaling pathways such as PI3K/AKT/mTOR and FOXO, influenced by transcription factor dysregulation, contribute to these conditions. In particular, the improper regulation of endothelial nitric oxide synthase (eNOS) and enhanced vascular smooth muscle cell proliferation highlight the interconnected nature of endothelial and smooth muscle dysfunction in diabetes. This relationship underscores the potential for targeting these pathways to alleviate both endothelial dysfunction and prevent the pathological remodeling that leads to vascular stiffness and hypertension.

Decline in Vascular Cell Stemness: The decline in the regenerative capacity of vascular cells is a critical concern, as it impacts the body’s ability to repair and regenerate vascular tissues. This study shows that diabetes-induced changes compromise the stemness of vascular progenitor cells, likely through alterations in the microenvironment that affect cellular differentiation and function. Addressing these changes is crucial for improving vascular repair mechanisms and managing long-term diabetic complications.

Therapeutic Opportunities and Future Directions: The findings suggest that enhancing the functionality of specific transcription factors and modulating associated signaling pathways could offer new therapeutic avenues. For instance, the use of Nrf2 activators or PI3K/AKT pathway modulators presents a strategy to counteract the oxidative stress and restore endothelial function in diabetic patients. Additionally, anti-inflammatory therapies could help mitigate the chronic inflammation seen in diabetic vascular disease.

Research Gaps: Despite these advances, several gaps remain. The exact molecular interactions between different transcription factors and their collective impact on vascular signaling pathways need further elucidation. Additionally, the long-term effects of modulating these transcription factors and signaling pathways in diabetic patients remain to be fully understood.

Key Findings:
The study points out the key roles of various transcription factors, such as KLFs, FOXC, and PAX, in mediating the effects of diabetes on vascular cells. Previously, the specific involvement of these transcription factors in diabetes-induced vascular dysfunction may not have been fully elucidated. Novel insights have also been uncovered into the mechanisms underlying the decline in stemness of vascular progenitor cells in diabetes, including the dysregulation of key transcription factors like PAX3/7 and FOXP1, which are critical for maintaining the regenerative capacity of vascular cells.

This study reveals the crucial interplay between different transcription factors in orchestrating the cellular responses to diabetes-induced stressors. This includes cross-talk between transcription factors such as NF-κB, SMAD, and Nrf2, which collectively contribute to vascular dysfunction. By investigating the downstream effects of transcription factor dysregulation, we have identified new targets for therapeutic intervention. For example, the aberrant activation of transcription factors like NF-κB and AP-1 leads to dysregulated signaling pathways, exacerbating vascular inflammation and oxidative stress. Overall, this study provides a more comprehensive understanding of the mechanisms underlying diabetes-induced vascular complications. This integrated view of vascular homeostasis highlights the importance of targeting transcription factor-mediated pathways for the development of novel therapeutic strategies aimed at mitigating the adverse effects of diabetes on vascular health. These new findings not only deepen our understanding of the pathophysiology of diabetic vascular complications but also offer promising avenues for future research and therapeutic interventions.

Implications of the study:

Based on the potential findings from the investigation of various transcription factors' roles in diabetes-induced vascular damage and the maintenance of stemness in vascular cells, several strategic implications can be drawn. These implications are significant for guiding future research and developing targeted therapeutic approaches. For instance, if Hypoxia-Inducible Factor 1-alpha (HIF-1α) is found to interact with the PI3K/AKT/FOXO pathway, therapeutic strategies could aim to enhance HIF-1α activity under hypoxic conditions to promote vascular repair and regeneration, particularly beneficial in treating ischemic injuries in diabetic patients. Additionally, discovering a role for Krüppel-Like Factors (KLFs) in linking metabolic regulation to stemness could lead to the development of drugs that enhance KLF activity, thereby improving the metabolic resilience and regenerative capacity of vascular stem cells. Further implications include targeting Nuclear Factor-kappa B (NF-κB) with inhibitors if its activation influences PI3K/AKT/FOXO signaling, to mitigate its pro-inflammatory effects, potentially reducing inflammation-induced vascular damage and preserving stem cell functionality. Understanding the integration of NOTCH signaling with PI3K/AKT/FOXO could lead to the use of NOTCH inhibitors or activators to balance stem cell renewal and differentiation, optimizing tissue repair processes in diabetic environments. Moreover, if Activator Protein-1 (AP-1) modulates PI3K/AKT/FOXO signaling, manipulating AP-1 activity could help modulate vascular stem cell responses to oxidative stress and other extracellular cues, improving their survival and functionality. Additionally, identifying interactions between ETS family transcription factors and the PI3K/AKT/FOXO pathway suggests that modulating ETS activity could influence vascular cell migration and differentiation, offering new approaches for enhancing vascular repair mechanisms. Discoveries related to FOXC factors regulating PI3K/AKT/FOXO signaling could pave the way for therapies that promote the stemness and differentiation potential of vascular cells, crucial for restoring damaged tissues. Elucidating the interaction between GATA factors and the PI3K/AKT/FOXO pathway could lead to novel interventions that precisely control lineage specification in vascular stem cells, enhancing their regenerative properties. If SMAD proteins are involved in modulating PI3K/AKT/FOXO signaling, targeting TGF-β/SMAD pathways might enhance the differentiation capacities of vascular progenitors, crucial for effective tissue regeneration. Enhancing Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) activity could bolster antioxidant defenses and improve the survival and regenerative capabilities of vascular stem cells, offering a protective strategy against oxidative stress in diabetes. Understanding how Paired Box (PAX) factors, specifically PAX3/7, affect PI3K/AKT/FOXO signaling could lead to methods that enhance the migration, differentiation, and integration of vascular cells into existing vascular structures, essential for vascular integrity. Lastly, insights into Forkhead Box Protein P1's (FOXP1) role in modulating PI3K/AKT/FOXO pathways could facilitate the development of interventions that enhance vascular cell survival, lineage specification, and adaptation to environmental stresses.

Clinical Implications of Research on Diabetes-Induced Vascular Dysfunction and Stemness Decline

1. Enhanced Therapeutic Targeting: This study elucidates the critical roles of various transcription factors in diabetes-induced vascular dysfunction, providing new targets for therapeutic interventions. For example, modulation of HIF-1α, KLFs, and Nrf2 could be tailored to enhance vascular repair mechanisms and protect against oxidative stress. Specifically targeting these transcription factors may lead to the development of pharmacological agents that directly address the underlying mechanisms of vascular deterioration in diabetic patients.

2. Improved Diagnostic Tools: Understanding the specific molecular changes that transcription factors undergo in diabetic vascular cells offers the potential to develop diagnostic markers that can detect early signs of vascular complications. This could lead to earlier interventions, potentially halting the progression of vascular diseases associated with diabetes.

3. Personalized Medicine Approaches: The findings support the concept of personalized medicine in the treatment of diabetes-related vascular issues. By identifying specific dysregulated pathways in individual patients, treatments can be more accurately tailored to counteract those specific dysfunctions. This approach could optimize therapeutic outcomes by targeting the molecular basis of each patient's disease profile.

4. Regenerative Medicine and Stem Cell Therapy: The insight gained into the decline in stemness of vascular cells under diabetic conditions opens new avenues for regenerative medicine. Future therapies might involve the use of stem cell technology to restore or replace dysfunctional vascular cells. Additionally, enhancing the stemness properties through genetic or pharmacological means could rejuvenate the regenerative capacity of these cells, offering a novel treatment modality for vascular repair.

5. Combination Therapies: Given the multifactorial nature of diabetes-induced vascular dysfunction, combining therapies that target different aspects of the disease—such as oxidative stress, inflammation, and endothelial dysfunction—might be more effective. For instance, a combination of anti-inflammatory agents, antioxidants, and drugs that enhance the functionality of specific transcription factors could provide a comprehensive treatment strategy that addresses various facets of vascular damage.

6. Long-term Management Strategies: Longitudinal studies based on the findings of this study could lead to the development of long-term management strategies for patients with diabetes, aiming to prevent or significantly delay the onset of vascular complications. This could involve routine monitoring of molecular markers identified in this study, along with early interventions tailored to the specific molecular dysfunctions observed.

7. Policy and Public Health Initiatives: The research could influence policy decisions and public health initiatives aimed at managing diabetes more effectively. Educating healthcare providers and patients about the importance of molecular monitoring in diabetes management could become a key component of public health strategies designed to reduce the burden of diabetic vascular diseases.

By continuously exploring and validating the roles of critical transcription factors and signaling pathways identified in this research, future studies can build on these findings to develop more effective, targeted, and comprehensive treatments for diabetes-induced vascular complications.

This study investigates how diabetes leads to significant damage in vascular cells and a decline in the stemness of these cells, critically undermining vascular homeostasis. Diabetes, characterized by chronic hyperglycemia and associated metabolic dysfunctions, exerts its detrimental effects through several interconnected pathways, ultimately disrupting the physiological functions of vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). Diabetes-induced dysregulations in critical transcription factors such as Nrf2, FOXP1, SMAD, PAX3/7, GATA, and FOXC have shown to play key roles in the decline of vascular health. These factors are essential for the maintenance of endothelial integrity, control of cellular proliferation, differentiation, response to oxidative stress, and inflammatory regulation within the vascular milieu. Impairment in these transcription factors due to diabetes leads to improper activation of downstream signaling pathways, including PI3K/AKT/mTOR and FOXO. Such disruptions contribute to endothelial dysfunction, impaired angiogenesis, and abnormal vascular remodeling—key features observed in the diabetic vasculature. The dysregulation of endothelial functions due to altered transcriptional control under diabetic conditions leads to reduced production of nitric oxide, increased vascular permeability, and enhanced leukocyte adhesion. These changes not only exacerbate vascular inflammation but also increase the risk of atherosclerosis, contributing to the overall cardiovascular complications associated with diabetes. Changes in the behavior of VSMCs, triggered by diabetes-induced transcriptional and signaling anomalies, result in phenotypic switching from contractile to synthetic types. This shift is marked by increased cellular proliferation, migration, and extracellular matrix production, fostering vascular stiffness and remodeling, crucial factors in the progression of atherosclerosis and hypertension.

Diabetes impacts the stemness of vascular cells, crucial for their regenerative capabilities. The altered microenvironment due to hyperglycemia, oxidative stress, and inflammation impairs the ability of vascular progenitor cells to differentiate effectively into functional endothelial or smooth muscle cells. This decline in cellular regenerative capacity contributes to the inability of the vascular system to repair itself, leading to chronic complications and impaired vascular regeneration. The findings underline the importance of targeting the molecular and cellular pathways affected by diabetes to restore vascular health. Strategies that enhance the function or expression of specific transcription factors, modulate key signaling pathways, and address the oxidative and inflammatory state of the vascular system could potentially reverse or mitigate the impact of diabetes on vascular health. Further research into specific mechanisms by which diabetes alters these transcription factors and signaling pathways will be crucial for developing targeted therapies that can effectively address the vascular complications associated with diabetes. The interplay between diabetes-induced molecular dysfunctions and vascular cell pathology is key to developing therapeutic interventions that can restore vascular homeostasis and improve clinical outcomes for patients suffering from diabetes.

HIF-1α - Hypoxia-Inducible Factor 1-alpha

KLFs - Krüppel-Like Factors

NF-κB - Nuclear Factor kappa-light-chain-enhancer of activated B cells

PI3K - Phosphoinositide 3-Kinase

AKT - Protein Kinase B (also known as AKT)

mTOR - Mechanistic Target Of Rapamycin

FOXO - Forkhead Box O

NOTCH - Notch Receptor Signaling Pathway

AP-1 - Activator Protein

FOXC - Forkhead Box C

GATA - GATA Binding Proteins

Nrf2 - Nuclear Factor Erythroid 2-Related Factor 2

PAX - Paired Box Transcription Factors

VECs - Vascular Endothelial Cells

VSMCs - Vascular Smooth Muscle Cells

TGF-β - Transforming Growth Factor Beta

eNOS - Endothelial Nitric Oxide Synthase

AGEs - Advanced Glycation End-products

Ethics declarations:
Ethics approval and consent to participate
Not applicable.

Consent for publication:
Not applicable.

Data Availability statement:
All data generated or analyzed during this study are included in this article.

Competing interests:
The authors declare that they have no competing interests.

Funding:
I declare that there was not any source of funding for this research work.

Acknowledgements:
“Not applicable”.

Authors’ Contribution:

1. Ovais Shafi (OS)* is the author of the study and was involved in the idea, concept, design, and methodology of the study, literature search and references. He did the writing, editing, and revision of the manuscript. He was involved in drawing the findings, results, conclusions, implications of the study, interpretation of the data and was involved in all aspects of the study. He prepared and wrote discussion, results, conclusions and all areas of the study. OS extracted and analyzed the data. He was involved in critical evaluation, audit of every aspect of the study, data extraction, adherence of the study to relevant PRISMA guidelines, limitations of the study, references, and all others. He was involved in drawing fig 1. The author read and approved the manuscript.
He investigated the vascular transcription factor-driven genetic switches for their roles in relation to this study:
HIF-1α, KLFs, NF-κB, NOTCH Signaling Transcription Factors, AP-1, ETS Family Transcription Factors, FOXC Transcription Factors, GATA Transcription Factors, SMAD Transcription Factors, Nrf2, PAX3/7, FOXP1.
Ovais Shafi (OS)*, MBBS - Sindh Medical College - Dow University of Health Sciences, Karachi, Pakistan. He aspires to become an eminent ‘Physician Scientist’. He is devoted to the research in disease development mechanisms, disease origins and therapeutics. OS is also passionate about multiple research areas including clinical trials, clinical medicine, therapeutics, regenerative medicine, precision medicine including gene therapies, finding disease specific targets for gene therapy, role of disease genomics and epigenetics in diagnosis, management, and therapeutics development. He is dedicated to the field of research and clinical medicine.
Email address*: [email protected]
Corresponding author: OS
Correspondence to Ovais Shafi

2. Saba Irfan (SI) is the co-author of the study. She contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections. She contributed to investigating the vascular transcription factor-driven genetic switches for their roles in relation to this study:
HIF-1α, KLFs, NF-κB, NOTCH Signaling Transcription Factors, AP-1, ETS Family Transcription Factors, FOXC Transcription Factors, GATA Transcription Factors, SMAD Transcription Factors, Nrf2, PAX3/7, FOXP1.
Dr. Saba Irfan MBBS, MD from Columbus, Ohio is an accomplished physician who graduated from Federal Medical and Dental College, Pakistan with extensive clinical experience across Pakistan, Canada, and the USA. Her interests lie in research studies, value-based medicine, and quality improvement initiatives. Currently pursuing a research fellowship affiliated with Michigan State University.

3. Aelia Ahmed (AA) is the co-author of the study. She contributed to the results of the study, also contributed to the writing and editing of the results section along with working on references. In the results, she contributed to investigating the vascular transcription factor-driven genetic switches for their roles in relation to this study:
HIF-1α, KLFs, NF-κB, NOTCH Signaling Transcription Factors, AP-1, ETS Family Transcription Factors, FOXC Transcription Factors, GATA Transcription Factors, SMAD Transcription Factors, Nrf2, PAX3/7, FOXP1.
Aelia Ahmed, MBBS - Sindh Medical College, Dow University of Health Science, Karachi Pakistan. She completed her House Job at Abbasi Shaheed hospital in Medicine and Surgery in 2018/2019. She has done rotations with: Dr Stuart B, Kipper M.D (Internal Medicine) San Diego CA USA, Mark Schecter M.D (Interventional Radiologist) San Diego CA USA, Dr Fareeha Siddiqui M.D (Oncologist) San Diego CA USA, Dr Abdul Rauf Chief of Neurosurgery at Saint Louis University Hospital, USA. Hands on training with Dr Syed Rizvi M.D (Endocrinologist), NJ Hamilton. Did observership with Dr Kemp M.D pediatric neurosurgery at Saint Louis university hospital in Missouri, USA. Shadowing with Dr Toshi in aesthetic medicine at Pavilion cosmetics, Sydney Australia in 2023. Her work experience includes: Covid Ward Emergency Doctor, RMO gynae/obs ward - IMET hospital (2020 - 2023). Founded and worked as an aesthetic medical physician in The Beauty Doc Co clinic Karachi, Pakistan (2022 - present).

4. Ganpat Maheshwari (GM) is the co-author of the study. He contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections. He contributed to investigating the vascular transcription factor-driven genetic switches for their roles in relation to this study:
HIF-1α, KLFs, NF-κB, NOTCH Signaling Transcription Factors, AP-1, ETS Family Transcription Factors, FOXC Transcription Factors, GATA Transcription Factors, SMAD Transcription Factors, Nrf2, PAX3/7, FOXP1.
Ganpat Maheshwari, MBBS - Sindh Medical College – Jinnah Sindh Medical University, Karachi, Pakistan. He is ECFMG-certified. He completed his medical school in 2021 and would be applying for Internal Medicine residency in United States. His future goal is to practice in Hospital Medicine in the United States.

5. Rajesh Kumar (RK) is the co-author of the study. He contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections. He contributed to investigating the vascular transcription factor-driven genetic switches for their roles in relation to this study:
HIF-1α, KLFs, NF-κB, NOTCH Signaling Transcription Factors, AP-1, ETS Family Transcription Factors, FOXC Transcription Factors, GATA Transcription Factors, SMAD Transcription Factors, Nrf2, PAX3/7, FOXP1.
Rajesh Kumar, MBBS - Sindh Medical College – Jinnah Sindh Medical University, Karachi, Pakistan. He is ECFMG Certified. He completed his medical school in 2021 and would be applying for Internal Medicine residency. His future goal is to become a competent Hospitalist in the United States.

6. Raveena (RA) is the co-author of the study. She contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections. She contributed to investigating the vascular transcription factor-driven genetic switches for their roles in relation to this study:
HIF-1α, KLFs, NF-κB, NOTCH Signaling Transcription Factors, AP-1, ETS Family Transcription Factors, FOXC Transcription Factors, GATA Transcription Factors, SMAD Transcription Factors, Nrf2, PAX3/7, FOXP1.
Raveena, MBBS - Sindh Medical College – Jinnah Sindh Medical University, Karachi, Pakistan. She is passionate about research in surgery and disease development mechanisms including neurodegenerative diseases, oncogenesis and others. She is ECFMG Certified. She is passionate about residency in Internal Medicine/Surgery. Her goal is to make significant impact in the field of Research.

7. Rahimeen Rajpar (RR) is the co-author of the study. She contributed to the findings, results and conclusions of the study, also contributed to the writing and editing of these sections along with working on references. She contributed to investigating the vascular transcription factor-driven genetic switches for their roles in relation to this study:
HIF-1α, KLFs, NF-κB, NOTCH Signaling Transcription Factors, AP-1, ETS Family Transcription Factors, FOXC Transcription Factors, GATA Transcription Factors, SMAD Transcription Factors, Nrf2, PAX3/7, FOXP1.
Rahimeen Rajpar (RR), MD is a dedicated medical professional with a passion for unraveling the mysteries of disease origins and progression. Currently pursuing her residency in internal medicine, RR harbors ambitions of specializing in oncology, with a focus on understanding and treating various forms of cancer. RR's commitment to advancing medical knowledge extends beyond the laboratory, she is working towards becoming a leader in the world of Medicine, looking at the medical intricacies from a different lens. Apart from research RR remains dedicated to improving the lives of her patients through comprehensive care and by working towards scientific discoveries.
RR is a MBBS graduate from Sindh Medical College – Jinnah Sindh Medical University, Karachi, Pakistan.

8. Ayesha Saeed (AS) is the co-author of the study. She contributed to the results of the study, also contributed to the writing and editing of the results section along with working on references. She contributed to investigating the vascular transcription factor-driven genetic switches for their roles in relation to this study:
HIF-1α, KLFs, NF-κB, NOTCH Signaling Transcription Factors, AP-1, ETS Family Transcription Factors, FOXC Transcription Factors, GATA Transcription Factors, SMAD Transcription Factors, Nrf2, PAX3/7, FOXP1.
Dr. Ayesha Saeed (AS) is a dedicated medical professional with a passion for gastroenterology. Holding a Doctor of Medicine degree from Dow University of Health Sciences, Pakistan. She has distinguished herself through exemplary clinical practice and a strong commitment to patient care and has a keen interest in digestive health and disease prevention. Driven by a desire to advance in the field, Dr. Ayesha is planning to pursue specialized fellowship in gastroenterology, aiming to enhance her expertise and contribute to innovative treatments for gastrointestinal disorders.

The work and contributions of everyone have been described in detail, the order is randomized and the numbering is just for referencing purpose.

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The authors declare no competing interests.

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Diabetes-Induced Vascular Dysfunction and Stemness Decline Investigated via Transcription Factor-Driven Genetic Switches

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