Aging and maternal dietary dietary deficiencies during pregnancy and lactation change cerebral and peripheral blood flow in adult female mice offspring following ischemic stroke to the sensorimotor cortex

doi:10.21203/rs.3.rs-2214082/v1

Download PDF

Article

Aging and maternal dietary dietary deficiencies during pregnancy and lactation change cerebral and peripheral blood flow in adult female mice offspring following ischemic stroke to the sensorimotor cortex

https://doi.org/10.21203/rs.3.rs-2214082/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

A maternal diet that provides adequate nutrition during pregnancy and lactation is vital to the neurodevelopment of offspring. One-carbon metabolism plays an important role in the closure of the neural tube of the developing embryo; however, the impact of maternal one-carbon dietary deficiencies on offspring neurological function later in life remains relatively unknown. Stroke is one of the leading causes of death globally, and its prevalence is expected to increase in younger age groups as the incidence of various risk factors for stroke increases (e.g., hypertension). The aim of our study was to determine the impact of maternal nutritional deficiencies on cerebral blood flow and peripheral hemodynamics after ischemic stroke in adult offspring. In this study, adult female C57BL/6J mice were placed on either control (CD), choline (ChDD) or folic acid (FADD) deficient diets for four weeks to deplete stores prior to mating and maintained on the assigned diet during pregnancy and lactation. Female offspring were weaned and transitioned to a CD for the duration of the study. Ischemic stroke was induced in the sensorimotor cortex of 2- and 10-month-old female offspring using the photothrombosis model. Six weeks after induction of stroke, cerebral and peripheral blood flow was measured using the Vevo2100 Pulse Wave Doppler tracing modality. Our data showed that 3.5-month-old female offspring from a ChDD mothers had reduced blood flow in the posterior cerebral artery compared to CD mice; this effect disappeared in older offspring. In 11.5-month-old females we observed changes in peripheral hemodynamics, but not in young animals. Our findings suggest that a maternal dietary deficiency in choline results in reduced cerebral blood flow in adult female offspring after ischemic stroke, but the long-term effects are not present. This result points to the key role of the maternal diet in early life neuro-programming, while emphasizing its effects on both fetal development and long-term cerebrovascular health.

Biological sciences/Neuroscience

Biological sciences/Neuroscience/Neural ageing

Biological sciences/Neuroscience/Neuro vascular interactions

Biological sciences/Physiology

Biological sciences/Physiology/Ageing

Biological sciences/Physiology/Neurophysiology

one-carbon metabolism

ischemic stroke

maternal diet

blood flow

Maternal nutrition during pregnancy and lactation is recognized as a critical factor determining the health of offspring [1–5]. Early life nutritional cofactors are critical for typical fetal development, but also in determining offspring disease outcome [6, 7]. The Developmental Origins of Health and Disease (DOHaD) theory suggests that prospective chronic diseases are programmed in utero [8–11]. When already compensating for fetal nutrient accumulation and increased maternal metabolic demands [12], altered or insufficient maternal nutrition impacts both early development and future offspring health. In offspring, maternal dietary deficiencies have been associated with ventricular septal defects [13] and impaired glucose tolerance [14], as well as modified neural tube closure [15, 16] and neurocognitive development [17–21]. Beyond this evidence of suboptimal structural development in offspring, maternal nutritional deficiencies have been linked to programming of offspring metabolic [22] and epigenetic [23–28] adaptations, thereby predisposing that individual to life-long cardiovascular, metabolic, and neuroendocrine dysfunction.

Epidemiological studies have demonstrated the effect of maternal diet on lifelong cardiovascular and neurological function [29–31]. Most of this population-level work reveals an effect of poor maternal health on birthweight and incidence of disease and cardiovascular risk factors in adulthood, such as hypertension and hyperlipidemia [4, 10]. Such relationships have been shown in numerous global populations and are apparent from birth through early childhood [32]. Folate and choline are important players in healthy fetal neurodevelopment due to their involvement in the closure of the neural tube and are components of one-carbon metabolism [33, 34]. Folate and its chemically synthesized form folic acid are important for fetal neurodevelopment [35], as folate requirements during pregnancy are increased by 5- to 10-fold compared to non-pregnant women [36]. Maternal folate and choline levels during pregnancy have also been shown to be important in the development of the cerebellum and hippocampus [37], as well as affecting postnatal myelination trajectories [38], short-term memory [39], hyperactivity/attention [40], neurocognitive development [41], and risk of autism spectrum disorder (ASD) [42].

Recent work in rodent models has improved mechanistic understanding of how maternal levels of folate and choline impact neurodevelopmental processes [43]. Akin to human epidemiological studies [29–31], murine maternal folate deficiencies have been implicated in adverse reproductive performance, implantation, and fetal growth [44]. During pregnancy and lactation, maternal dietary folic acid availability has been shown to influence progenitor cell mitosis, and apoptosis in the fetal mouse forebrain [45] and hippocampus [39]. Investigations of maternal perinatal folate deficiencies have revealed reduced hippocampal proliferation, impaired vesicular transport and synaptic plasticity, as well as poor neurite outgrowth [46], modified cellular neocortex composition, and diminished complexity and arborization of projection neurons [47] in offspring. In addition to these structural observations, both genetic and epigenetic modifications have been observed; maternal folate deficiencies reduced expressions levels of brain derived neurotropic factor (BDNF) and H3K9me2 in the fetal hippocampus, and folic acid deficiency for two generations, significantly enhancing de novo mutations accumulation during meiosis [48]. Choline, another one-carbon cofactor implicated in a number of diverse biological processes [49], has yielded variable results in animal models of neurodevelopment. Effects of maternal choline deficiencies, such as defective layering of the cortex, reduced cortical size and brain weight [50], and modified hippocampal electrophysiology [51] and neurogenesis [52], have been observed in offspring. Beyond these physiological, and histological findings, choline and folate deficiencies have been shown to elicit similar adverse effects, such as impaired homocysteine remethylation, oxidative stress, and endothelial dysfunction in murine cerebrovasculature (59,60); effectively demonstrating the link between maternal one-carbon cofactors and typical fetal neurodevelopment.

The link between maternal nutrition and fetal development is abundantly clear, but the long-term effects of maternal nutritional deficiencies on adult offspring are less well-studied. Investigating the links between cerebral and peripheral blood flow and the maternal environment will improve our understanding of dietary requirements during pregnancy and provide information on the role of maternal nutrition in early life programming of adult neurovascular diseases, such as ischemic stroke. Stroke is among the leading causes of death globally and its prevalence as a major health concern is predicted to increase, as the global population ages and demographics of populations change [53, 54]. One of the many reasons these problems exist is that the majority of preclinical studies are targeted only towards male subjects [55]. Over 90% of preclinical studies use strictly male mice whereas all clinical studies use equal part male and female participants [55, 56]. This makes clinical pharmaceutical findings favor better outcomes in males [57, 58]. The aim of this study was to determine the impact of perinatal maternal nutritional deficiencies in folic acid or choline on cerebral and peripheral (cardiac and aortic) hemodynamics flow after ischemic stroke in adult and mid-age female offspring.

Cerebral blood flow in offspring after ischemic stroke

In 3.5-month-old offspring, there was a statistically significant difference in blood flow velocity within the posterior cerebral artery (Fig. 1A) between maternal dietary groups (Fig. 1B; F (2, 15) = 4.07, p = 0.04). Female offspring of ChDD mothers had significantly impaired blood flow velocity in the PCA compared to offspring from the CD group (p = 0.04). A maternal FADD reduced blood flow velocity in female offspring, but this did not reach significance (p = 0.14). In 11.5-month-old offspring, no statistically significant differences in cerebral blood flow velocity were observed between maternal diet groups (Fig. 1C; F [2, 13] = 4.07, p = 0.08).

Cardiac/Aortic (Peripheral) hemodynamics in offspring after ischemic stroke

In 3.5-month-old offspring, no differences in cardiac/aortic (peripheral) hemodynamics were observed between maternal diet groups (Table 1). In 11.5-month-old offspring, there was a statistically significant difference in the coronary artery velocity ratio between maternal diet groups (Table 2; F (2, 13) = 4.07, p = 0.08). Female offspring of FADD mothers had a significantly increased systolic/diastolic ratio in the coronary artery compared to controls.

Table 1

Descriptive statistics (Mean ± SEM) of peripheral hemodynamics in 3.5-month-old female mouse offspring by maternal diet. Maternal diets included a control diet (CD), a folic acid deficient diet (FADD), and a choline deficient diet (ChDD). Mean ± SEM of 5 to 7 mice per group.
	Maternal Diet
Measurement	CD	FADD	ChDD	p-value
Average Heart Rate (BPM)	494.2 ± 13.23	504.5 ± 12.68	513.0 ± 9.55	0.57
Average Stroke Volume (uL)	24.04 ± 2.54	28.67 ± 2.17	25.26 ± 2.06	0.33
Average Ejection Fraction (%)	86.57 ± 4.24	84.68 ± 3.09	86.46 ± 2.3	0.90
Average Fractional Shortening (%)	57.94 ± 6.28	53.89 ± 3.67	54.89 ± 3.13	0.81
Average Cardiac Output (mL/min)	11.77 ± 1.04	14.43 ± 1.08	12.94 ± 1.03	0.22
Coronary Artery Velocity Ratio (S/D)	0.34 ± 0.05	0.29 ± 0.02	0.36 ± 0.14	0.40
Aortic Pulse Wave Velocity (mm·s^− 1)	1.23 ± 0.24	3.52 ± 1.95	4.24 ± 3.28	0.57
Left Internal Diameter in Systolic (IVSs)	173.7 ± 28.62	163.7 ± 18.58	125.4 ± 19.83	0.42
Left Internal Diameter in Diastolic (IVSd)	531.2 ± 83.17	574.5 ± 45.33	361.9 ± 53.26	0.11

Table 2

Descriptive statistics (Mean ± SEM) of peripheral hemodynamics in 11.5-month-old female mouse offspring by maternal diet. Maternal diets included a control diet (CD), a folic acid deficient diet (FADD), and a choline deficient diet (ChDD). Mean ± SEM of 5 to 7 mice per group.
	Maternal Diet
Measurement	CD	FADD	ChDD	p-value
Average Heart Rate (BPM)	524.8 ± 8.82	531.4 ± 4.02	531.3 ± 6.02	0.64
Average Stroke Volume (uL)	23.55 ± 4.55	37.47 ± 5.56	38.24 ± 2.08	0.05
Average Ejection Fraction (%)	84.88 ± 3.55	85.05 ± 2.85	74.93 ± 4.24	0.10
Average Fractional Shortening (%)	53.65 ± 4.18	53.92 ± 3.88	43.70 ± 4.04	0.11
Average Cardiac Output (mL/min)	20.32 ± 0.78	19.91 ± 2.97	20.28 ± 0.96	0.90
Coronary Artery Velocity Ratio (S/D)	0.27 ± 0.02	0.39 ± 0.04	0.28 ± 0.02	0.04*
Aortic Pulse Wave Velocity (mm·s^− 1)	3.28 ± 0.46	5.52 ± 2.83	6.11 ± 2.28	0.52
Left Internal Diameter in Systolic (IVSs)	90.72 ± 29.49	159.3 ± 27.05	167.5 ± 26.45	0.18
Left Internal Diameter in Diastolic (IVSd)	663.0 ± 72.03	427.8 ± 62.76	545.6 ± 58.14	0.10

The impact of aging on cerebral blood flow and cardiac/aortic hemodyamics

We compared the 3.5 and 11.5-month female cerebral and cardiac/aortic (peripheral) hemodynamics measurements (Table 3). For fractional shortening and end systole septal diameter, no differences were observed between experimental groups. However, further analysis revealed significant effects on other peripheral hemodynamic measures. Main effects of diet (p = 0.03) and offspring age (p = 0.001) were observed for average heart rate. While exclusively offspring age effects were observed for ejection fraction (p = 0.01), cardiac output (p < 0.0001), and pulse wave velocity (p < 0.0001). Finally, significant interaction effects were observed for stroke volume (p = 0.03), coronary artery velocity ratio (p = 0.02), and end diastole septal diameter (p = 0.04).

Table 3

Descriptive statistics (Mean ± SEM) of central and peripheral blood flow in 3.5 and 11.5-month-old female mouse offspring. Maternal diets included a control diet (CD), a folic acid deficient diet (FADD), and a choline deficient diet (ChDD). Mean ± SEM of 5 to 7 mice per group.
		Offspring Age		p-values
Measurement	Maternal Diet	3.5 months	11.5 months	Diet	Age	Diet x Age
Posterior Cerebral Artery (mm/s)	CD FADD ChDD	147.74 + 10.24 136.43 + 8.78 109.74 + 4.38	122.37 _ 9.24 146.27 + 21.01 99.62 + 8.4	0.009	0.37	0.30
Average Heart Rate (BPM)	CD	474.53 ± 15.19	524.78 ± 8.82	0.03*	0.001*	0.1374
	FADD	515.96 ± 5.84	531.42 ± 4.02
	ChDD	511.16 ± 11.30	531.30 ± 6.02
Average Stroke Volume (uL)	CD	24.04 ± 2.54	23.55 ± 4.55	0.2744	0.2319	0.03*
	FADD	28.67 ± 2.17	37.47 ± 5.56
	ChDD	25.26 ± 2.06	38.24 ± 2.08
Average Ejection Fraction (%)	CD	86.58 ± 4.24	84.88 ± 3.55	0.1638	0.009*	0.2929
	FADD	84.68 ± 3.09	73.10 ± 4.61
	ChDD	86.46 ± 2.30	74.05 ± 2.49
Average Fractional Shortening (%)	CD	57.94 ± 6.28	53.65 ± 4.18	0.3924	0.1811	0.4998
	FADD	53.89 ± 3.67	53.92 ± 3.88
	ChDD	54.89 ± 3.13	43.70 ± 4.04
Average Cardiac Output (mL/min)	CD	11.77 ± 1.04	20.32 ± 0.78	0.7197	< 0.0001*	0.5400
	FADD	14.43 ± 1.08	19.91 ± 2.94
	ChDD	12.94 ± 1.03	20.28 ± 0.96
Coronary Artery Velocity Ratio (S/D)	CD	0.32 ± 0.04	0.27 ± 0.02	0.3813	0.9454	0.02*
	FADD	0.29 ± 0.02	0.39 ± 0.04
	ChDD	0.36 ± 0.07	0.28 ± 0.02
Pulse Wave Velocity (mm·s^− 1)	CD	1.23 ± 0.24	3.29 ± 0.46	0.8061	< 0.0001*	0.1498
	FADD	1.58 ± 0.18	2.71 ± 0.36
	ChDD	0.97 ± 0.18	3.92 ± 0.74
Left Internal Diameter in Systolic (IVSs)	CD	173.72 ± 28.62	180.53 ± 24.50	0.4980	0.4745	0.6540
	FADD	163.72 ± 18.58	159.27 ± 27.05
	ChDD	125.35 ± 19.83	167.50 ± 26.45
Left Internal Diameter in Diastolic (IVSd)	CD	531.18 ± 83.17	662.98 ± 72.03	0.1063	0.3048	0.03*
	FADD	574.46 ± 45.33	427.78 ± 62.76
	ChDD	361.92 ± 53.26	545.59 ± 58.14

The Developmental Origins of Health and Disease (DOHaD) theory suggests that prospective chronic diseases are programmed in utero- giving rise to programming of offspring cardiovascular, metabolic, and neuroendocrine dysfunction [8–11]. Despite impressive evidence of the importance of the maternal environment for fetal growth and development, there have been few investigations surrounding the effects of maternal nutrition on cerebrovascular function in fully developed or adult offspring. Using an experimental model of ischemic stroke, our study aimed to determine the impact of perinatal maternal nutritional deficiencies in 1C metabolites on measures of cerebral and peripheral blood flow and cardiac function in offspring, following ischemic injury. Our results demonstrate a significant impairment in cerebral blood flow velocity following stroke in 3.5-month-old, but not 11.5-month-old offspring from choline-deficient mothers. However, 11.5-month-old offspring from folic acid-deficient mothers did display a significant increase in peripheral hemodynamic measures, including the coronary artery velocity ratio. Effects of both diet and offspring age, as well as interactions between these variables were observed for numerous peripheral indices.

The neurovascular unit (NVU) is comprised of a number of unique neuronal, glial, and endothelial cell types, and recent findings indicate unique cross-talk between neurons and the cerebral vasculature [69–72], emphasizing the complex, pivotal role the NVU plays during development and in the progression of neurovascular pathologies like ischemic stroke and neurodegenerative disorders [73–78]. Further, the NVU is responsible for the maintenance of a highly selective blood–brain barrier (BBB) and cerebral homeostasis, as well as the control of cerebral blood flow (CBF) [79]. The impact of maternal diet on the NVU, modulating integrity of cerebral blood vessels and closure of the neural tube, has been established [15, 16, 80–82]. Our study adds to these investigations by assessing the hemodynamic response of blood flow within the posterior cerebral artery (PCA) in both young and aged offspring. The contralesional PCA was selected as an index of cerebral blood flow due to its spatial and functional independence from the sensorimotor cortex targeted during photothrombotic stroke [83], and evident correlation to measures of the Middle Cerebral Artery (MCA) [84].

In line with studies detailing the impact of maternal choline on neurovascular development [16], our results suggest that maternal choline levels during pregnancy and lactation impair cerebral blood flow in young mice following ischemic stroke. In rodent models, the importance of choline for optimal neurodevelopment is well-established [85, 86]. Recent work has examined the role of choline in neurovascular interactions as well, modulating levels of anti-angiogenic factors during gestation [87], fetal hippocampal angiogenesis [37], and promoting the proliferation of rat endothelial cells following hypoxic injury in cerebral vessels [88]. In this way, choline has been shown to influence neurovascular health across the lifespan and may be implicated in both neurovascular structure and functional response to injury. The cardiovascular system has also demonstrated effects of choline deficiency, including heart defects [89, 90], while higher intake of choline was associated with reduced risk of adult cardiovascular disease [91] and amelioration of impaired vagal activity and inflammation in hypertensive rodents [92]. Our study revealed a diet effect of both maternal choline and folic acid, where deficiencies in either nutrient significantly increased offspring heart rate, regardless of offspring age. While heart rate is a well-known risk factor for cardiovascular disease, our results align well with recent findings associating low heart rate with better functional and cognitive outcomes following ischemic stroke [93] and high heart rate with impaired endothelial function and increased ischemic lesion size following stroke [94], as well as death due to vascular diseases [93]. Overall, maternal diet has an established developmental influence on basic measures of cardiovascular and neurovascular health, and may impact offspring programming of the NVU, thereby influencing stroke protection via endothelial homeostasis via endothelial NO synthase (eNOS) [95, 96].

We did not observe an effect of maternal diet on cerebral blood flow in 11.5-month-old offspring. This could be due to the well-investigated aging-associated changes in the structural and functional integrity of the vasculature [97–101]. Therefore, we propose that the difference in effect between young (3.5m.o.) and old (11.5m.o.) offspring is a result of the aging of the control mice. In addition, the presumed damage or endothelial dysfunction induced by the deficient diets is long-lasting and may contribute to premature aging, generating a mathematically significant difference when compared to young, healthy controls, but only a minor difference when compared to senescent offspring displaying similar levels of vascular dysfunction. This result is supported by the interaction effect of diet and offspring age and requires further investigation. In addition, unique mechanisms drive vascular senescence in males and females [102], so our results may be obscured by our study of exclusively female mice. Another interesting result from our study is the significance of the coronary artery velocity (S/D) ratio in 11.5-month-old offspring. In this assessment, folic acid significantly increased the ratio, as occurs with moderate coronary atherosclerosis [103]. This result may indicate cardiovascular impairment related to a maternal diet deficient in choline. However, because the incidence of coronary artery disease (CAD), valvular disease, rhythm disorders, and heart failure increases with age [104], it appears that folic acid may play a role in programming resistance to this age-related dysfunction.

Outside of heart rate, which is discussed above, age effects were observed for offspring ejection fraction, cardiac output, and pulse wave velocity. Ejection fraction, an index of the left ventricular output, has recently been used as a measure of cardiac mortality risk [105], with lower percentages indicating cardiac dysfunction. In our study, older mice displayed a significantly reduced ejection fraction, indicating cardiovascular impairment. In a similar manner, our cardiac output data indicate the expected increased cardiac dysfunction as a product of aging [106]. Aortic pulse wave velocity (PWV) was also found to be significantly increased on the older cohort, in line with clinical findings [107]. Finally, interactions between maternal folic acid deficiency and offspring age were found for the coronary artery velocity S/D ratio, an indicator of coronary atherosclerosis, and interventricular septal end diastole (IVSd), an indicator of ventricular hypertrophy.

Overall, our data points to the need for rodent models spanning a variety of ages for research in age-related diseases such as stroke and vascular dysfunction. We recognize that the exclusion of male subjects in this study may limit our ability to draw conclusions with respect to the impact of sex hormone in observed phenomenon. In future studies, we plan to include male animals, and design experiments that would allow us to investigate the role of paternal dietary effects. Additionally, we plan to further age animals to ~ 20mo after ischemic stroke as well as investigate the role of over supplementation on blood flow after stroke. A detailed analysis of angiogenesis after ischemic stroke might also be prudent. In conclusion, 1C metabolism metabolites have potentially compensatory, but unique roles. Maternal nutrition during pregnancy and lactation has effects, even after infancy and childhood. Our work demonstrated an age effect in animal models encourages further comprehensive longitudinal time-point studies that includes older age animals.

Experimental Design

All animal experimentation was performed following approval by the Midwestern University Institutional Animal Care and Use Committee (Protocol 2983) in accordance with animal welfare and ARRIVE guidelines.

Experimental manipulations are summarized in Fig. 2. Briefly, for the maternal cohort (n = 30) female and (n = 30) male C57BL/6J mice were purchased from Jackson Laboratories and acclimatized for one week to controlled housing conditions (22 ± 1°C, 12h-light/12h-dark cycle) with ad libitum access to food and water (RRID: IMSR_JAX:000664, Jackson Laboratories). At two months of age (Day 0), females were randomized to control (CD, TD.190790), and commercially (Envigo) prepared folic acid (FADD, TD.01546) or choline deficient (ChDD, TD.06119) diets and maintained on these diets for four weeks prior to mating, and later throughout pregnancy and lactation (Fig. 1). Levels of folic acid and choline bitartrate in experimental diets are listed in in Table 4 [39, 59–61].

Table 4

Experimental Diets. Concentration (in milligrams/kilogram) of folic acid and choline bitartrate in control (CD), folic acid-deficient (FADD), and choline-deficient (ChDD) diets fed to mothers throughout pregnancy and lactation.
	Diet
	Control	FADD	ChDD
Folic Acid (mg/kg)	2	0.3	2
Choline Bitartrate (mg/kg)	1150	1150	300

After weaning, female offspring were maintained on the CD ad libitum. Offspring were randomized to one of two cohorts undergoing photothrombotic (PT) stroke at either 2- or 10-months of age, followed by ultrasound measurements at 1.5 months post-stroke.

Photothrombosis

When female offspring reached 2 or 10 months of age, ischemia was induced using the photothrombosis model. They were anesthetized with isoflurane (1.5%) in a 70:30 nitrous oxide:oxygen mixture. Core body temperature was monitored with a rectal thermometer (Harvard Apparatus) and maintained at 37 ± 0.2 ºC using a heating blanket. 10 mg/kg of the photosensitive Rose Bengal dye was injected intraperitoneally 5 minutes prior to irradiation. A 532 nm green laser was placed 3 cm above the animal and directed to the sensorimotor cortex (mediolateral + 0.24mm) for 15 minutes [59, 62–64].

Ultrasound imaging

Approximately 1.5 months after ischemic stroke, Vevo® 2100 ultrasound imaging system (FUJIFILM, Visual Sonics) was used to assess offspring in vivo cerebral, posterior cerebral artery (PCA; Fig. 1A) and peripheral vascular function as previously reported [65, 66]. Measurements were completed in random order by investigators blinded to treatment groups. The high-frequency, high-resolution ultrasound system is equipped with a 40 MHz transducer (MS550S) with a focal length of 7.0 mm, frame rate of 557 fps (single zone, 5.08 mm width, B-mode), and a maximum two-dimensional field of view of 14.1×15.0 mm with a spatial resolution of 90 µm lateral by 40 µm axial.

Mice were anesthetized in an induction chamber with 3% isoflurane and 1 L/min flow of 100% oxygen for 1–2 mins, then placed supine on a heated platform and maintained with 1.5–2% isoflurane. Heart rate, electrocardiogram (ECG), and respiratory rate were measured by the four ECG electrodes embedded in the platform. Using a heat lamp and heated platform, body temperature was maintained at 36–38°C and monitored by a rectal probe throughout.

The left ventricular (LV) structural and functional parameters, including stroke volume, ejection fraction, fractional shortening, and cardiac output, were calculated from the LV parasternal short-axis M-mode view and recorded at the level of two papillary muscles. An M-mode cursor was positioned perpendicular to the anterior and posterior walls in the middle of the LV for measuring wall thickness. Interventricular septal wall (IVS) thickness during diastole (IVSd) and systole (IVSs) were also obtained from LV parasternal long-axis M-mode view.

Aortic diameters at the annulus, sinuses of Valsalva, and sinotubular junctions were measured from the B-mode aortic arch view. Ascending and descending aortic, and posterior cerebral artery (PCA) peak velocities were measured from the pulse wave (PW) Doppler-mode. Pulse wave velocity (PWV) was obtained from the B-mode and Doppler-mode aortic arch view, calculated as PWV (mm·s − 1) = aortic arch distance (d2-d1)/transit time (T1-T2). The PW Doppler mode sample volume was placed in the ascending aorta to verify the time from the onset of the QRS complex to the onset of the ascending aortic Doppler waveform (T1). Using the same image plane, the time from the onset of the QRS complex to the onset of the descending aortic Doppler waveform (T2) was also measured, and the average values for T1 and T2 over 10 cardiac cycles were calculated. Furthermore, the aortic arch distance was measured between the two sample volume positions along the central axis of aortic arch on the B-mode image.

Transcranial Doppler sonography is a non-invasive, non‐ionizing, inexpensive, portable, and safe technique that uses a pulsed Doppler transducer for assessment of intracerebral blood flow in the clinical practice [67, 68] and has become an important translational tool to evaluate the intracerebral blood flow in animal models.

The PCA peak blood flow was measured using the Vevo 2100 high-resolution ultrasound system and the 24MHz (MS250) transducer. The trans occipital window was used to visualize the posterior cerebral arteries and pulsed wave (PW), Doppler-mode was used to measure the PCA peak blood flow velocity.

Statistics

Ultrasound data was analyzed by two individuals that were blinded to experimental treatment groups using Vevo Lab ultrasound analysis software (VisualSonics, Toronto, Canada). Using GraphPad Prism 9.0., One-way ANOVA analysis was performed to analyze maternal dietary effects, and two-way ANOVA analysis was performed to assess aging effects. Significant main effects of two-way ANOVAs were followed up with Tukey’s post-hoc test to adjust for multiple comparisons. All data are presented as mean ± standard error of the mean (SEM). Statistical tests were performed using a significance level (P) of 0.05.

Acknowledgments

Grants awarded to Mitra Esfandiarei; R15HL145646 (NIH) and Nafisa M. Jadavji; 20AIREA35050015 (American Heart Association; 20AIREA35050015)

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data availability statement –

Data is available within supplementary files. Nafisa Jadavji, corresponding author can be contacted for all data requests related to this study.

Author Contributions

Kasey Pull: data analysis, writing – original draft, writing – review and editing. Robert Folk: investigation and data analysis. Jeemin Kang: data analysis. Shaley Jackson: data analysis. Brikena Gusek: investigation and data analysis. Mitra Esfandiareri: Conceptualization, writing – review and editing, funding acquisition. Nafisa M. Jadavji: conceptualization, investigation, resources, data curation, writing – original draft, writing – review and editing, visualization, supervision, project administration, and funding acquisition

Gernand, A.D.; Schulze, K.J.; Stewart, C.P.; West, K.P.; Christian, P. Micronutrient Deficiencies in Pregnancy Worldwide: Health Effects and Prevention. Nat. Rev. Endocrinol. 2016, 12, 274–289, doi:10.1038/nrendo.2016.37.
Badon, S.E.; Miller, R.S.; Qiu, C.; Sorensen, T.K.; Williams, M.A.; Enquobahrie, D.A. Maternal Healthy Lifestyle during Early Pregnancy and Offspring Birthweight: Differences by Offspring Sex. J. Matern.-Fetal Neonatal Med. Off. J. Eur. Assoc. Perinat. Med. Fed. Asia Ocean. Perinat. Soc. Int. Soc. Perinat. Obstet. 2018, 31, 1111–1117, doi:10.1080/14767058.2017.1309383.
Lu, M.-S.; Chen, Q.-Z.; He, J.-R.; Wei, X.-L.; Lu, J.-H.; Li, S.-H.; Wen, X.-X.; Chan, F.-F.; Chen, N.-N.; Qiu, L.; et al. Maternal Dietary Patterns and Fetal Growth: A Large Prospective Cohort Study in China. Nutrients 2016, 8, E257, doi:10.3390/nu8050257.
Ae-Ngibise, K.A.; Wylie, B.J.; Boamah-Kaali, E.; Jack, D.W.; Oppong, F.B.; Chillrud, S.N.; Gyaase, S.; Kaali, S.; Agyei, O.; Kinney, P.L.; et al. Prenatal Maternal Stress and Birth Outcomes in Rural Ghana: Sex-Specific Associations. BMC Pregnancy Childbirth 2019, 19, 391, doi:10.1186/s12884-019-2535-9.
Borge, T.C.; Aase, H.; Brantsæter, A.L.; Biele, G. The Importance of Maternal Diet Quality during Pregnancy on Cognitive and Behavioural Outcomes in Children: A Systematic Review and Meta-Analysis. BMJ Open 2017, 7, e016777, doi:10.1136/bmjopen-2017-016777.
Warner, M.J.; Ozanne, S.E. Mechanisms Involved in the Developmental Programming of Adulthood Disease. Biochem. J. 2010, 427, 333–347, doi:10.1042/BJ20091861.
Steegers-Theunissen, R.P.; Obermann-Borst, S.A.; Kremer, D.; Lindemans, J.; Siebel, C.; Steegers, E.A.; Slagboom, P.E.; Heijmans, B.T. Periconceptional Maternal Folic Acid Use of 400 Μg per Day Is Related to Increased Methylation of the IGF2 Gene in the Very Young Child. PLOS ONE 2009, 4, e7845, doi:10.1371/journal.pone.0007845.
Barker, D.J.P.; Osmond, C. INFANT MORTALITY, CHILDHOOD NUTRITION, AND ISCHAEMIC HEART DISEASE IN ENGLAND AND WALES. The Lancet 1986, 327, 1077–1081, doi:10.1016/S0140-6736(86)91340-1.
Barker, D.J.P.; Osmond, C.; Winter, P.D.; Margetts, B.; Simmonds, S.J. WEIGHT IN INFANCY AND DEATH FROM ISCHAEMIC HEART DISEASE. The Lancet 1989, 334, 577–580, doi:10.1016/S0140-6736(89)90710-1.
Barker, D.J.P.; Godfrey, K.M.; Gluckman, P.D.; Harding, J.E.; Owens, J.A.; Robinson, J.S. Fetal Nutrition and Cardiovascular Disease in Adult Life. The Lancet 1993, 341, 938–941, doi:10.1016/0140-6736(93)91224-A.
Barker, D. Intrauterine Programming of Coronary Heart Disease and Stroke. Acta Paediatr. 1997, 86, 178–182, doi:10.1111/j.1651-2227.1997.tb18408.x.
Christian, P.; Stewart, C.P. Maternal Micronutrient Deficiency, Fetal Development, and the Risk of Chronic Disease. J. Nutr. 2010, 140, 437–445, doi:10.3945/jn.109.116327.
Song, X.; Wei, J.; Shu, J.; Liu, Y.; Sun, M.; Zhu, P.; Qin, J. Association of Polymorphisms of FOLR1 Gene and FOLR2 Gene and Maternal Folic Acid Supplementation with Risk of Ventricular Septal Defect: A Case-Control Study. Eur. J. Clin. Nutr. 2022, doi:10.1038/s41430-022-01110-9.
Ravelli, A.; van der Meulen, J.; Michels, R.; Osmond, C.; Barker, D.; Hales, C.; Bleker, O. Glucose Tolerance in Adults after Prenatal Exposure to Famine. The Lancet 1998, 351, 173–177, doi:10.1016/S0140-6736(97)07244-9.
Pitkin, R.M. Folate and Neural Tube Defects. Am. J. Clin. Nutr. 2007, 85, 285S-288S, doi:10.1093/ajcn/85.1.285S.
Shaw, G.M.; Carmichael, S.L.; Yang, W.; Selvin, S.; Schaffer, D.M. Periconceptional Dietary Intake of Choline and Betaine and Neural Tube Defects in Offspring. Am. J. Epidemiol. 2004, 160, 102–109, doi:10.1093/aje/kwh187.
Nyaradi, A.; Li, J.; Hickling, S.; Foster, J.; Oddy, W.H. The Role of Nutrition in Children’s Neurocognitive Development, from Pregnancy through Childhood. Front. Hum. Neurosci. 2013, 7, 97, doi:10.3389/fnhum.2013.00097.
Wachs, T.D. Nutritional Deficits and Behavioural Development. Int. J. Behav. Dev. 2000, 24, 435–441, doi:10.1080/016502500750037982.
Georgieff, M.K. Nutrition and the Developing Brain: Nutrient Priorities and Measurement. Am. J. Clin. Nutr. 2007, 85, 614S-620S, doi:10.1093/ajcn/85.2.614S.
Georgieff, M.K.; Ramel, S.E.; Cusick, S.E. Nutritional Influences on Brain Development. Acta Paediatr. Oslo Nor. 1992 2018, 107, 1310–1321, doi:10.1111/apa.14287.
Caffrey, A.; McNulty, H.; Rollins, M.; Prasad, G.; Gaur, P.; Talcott, J.B.; Witton, C.; Cassidy, T.; Marshall, B.; Dornan, J.; et al. Effects of Maternal Folic Acid Supplementation during the Second and Third Trimesters of Pregnancy on Neurocognitive Development in the Child: An 11-Year Follow-up from a Randomised Controlled Trial. BMC Med. 2021, 19, 73, doi:10.1186/s12916-021-01914-9.
Huang, R.-C.; Mori, T.A.; Beilin, L.J. Early Life Programming of Cardiometabolic Disease in the Western Australian Pregnancy Cohort (Raine) Study. Clin. Exp. Pharmacol. Physiol. 2012, 39, 973–978, doi:10.1111/j.1440-1681.2012.05746.x.
Heijmans, B.T.; Tobi, E.W.; Stein, A.D.; Putter, H.; Blauw, G.J.; Susser, E.S.; Slagboom, P.E.; Lumey, L.H. Persistent Epigenetic Differences Associated with Prenatal Exposure to Famine in Humans. Proc. Natl. Acad. Sci. 2008, 105, 17046–17049, doi:10.1073/pnas.0806560105.
Dominguez-Salas, P.; Cox, S.E.; Prentice, A.M.; Hennig, B.J.; Moore, S.E. Maternal Nutritional Status, C1 Metabolism and Offspring DNA Methylation: A Review of Current Evidence in Human Subjects. Proc. Nutr. Soc. 2012, 71, 154–165, doi:10.1017/S0029665111003338.
James, P.; Sajjadi, S.; Tomar, A.S.; Saffari, A.; Fall, C.H.D.; Prentice, A.M.; Shrestha, S.; Issarapu, P.; Yadav, D.K.; Kaur, L.; et al. Candidate Genes Linking Maternal Nutrient Exposure to Offspring Health via DNA Methylation: A Review of Existing Evidence in Humans with Specific Focus on One-Carbon Metabolism. Int. J. Epidemiol. 2018, 47, 1910–1937, doi:10.1093/ije/dyy153.
Bokor, S.; Vass, R.A.; Funke, S.; Ertl, T.; Molnár, D. Epigenetic Effect of Maternal Methyl-Group Donor Intake on Offspring’s Health and Disease. Life 2022, 12, 609, doi:10.3390/life12050609.
Peter, C.J.; Fischer, L.K.; Kundakovic, M.; Garg, P.; Jakovcevski, M.; Dincer, A.; Amaral, A.C.; Ginns, E.I.; Galdzicka, M.; Bryce, C.P.; et al. DNA METHYLATION SIGNATURES OF EARLY CHILDHOOD MALNUTRITION ASSOCIATED WITH IMPAIRMENTS IN ATTENTION AND COGNITION. Biol. Psychiatry 2016, 80, 765–774, doi:10.1016/j.biopsych.2016.03.2100.
Guéant, J.-L.; Namour, F.; Guéant-Rodriguez, R.-M.; Daval, J.-L. Folate and Fetal Programming: A Play in Epigenomics? Trends Endocrinol. Metab. 2013, 24, 279–289, doi:10.1016/j.tem.2013.01.010.
Arima, Y.; Fukuoka, H. Developmental Origins of Health and Disease Theory in Cardiology. J. Cardiol. 2020, 76, 14–17, doi:10.1016/j.jjcc.2020.02.003.
Forsdahl, A. Living Conditions in Childhood and Subsequent Development of Risk Factors for Arteriosclerotic Heart Disease. The Cardiovascular Survey in Finnmark 1974-75. J. Epidemiol. Community Health 1978, 32, 34–37, doi:10.1136/jech.32.1.34.
Thornburg, K.L.; O’Tierney, P.F.; Louey, S. Review: The Placenta Is a Programming Agent for Cardiovascular Disease. Placenta 2010, 31 Suppl, S54-59, doi:10.1016/j.placenta.2010.01.002.
Law, C.M.; Shiell, A.W. Is Blood Pressure Inversely Related to Birth Weight? The Strength of Evidence from a Systematic Review of the Literature. J. Hypertens. 1996, 14, 935–941.
McKee, S.E.; Reyes, T.M. Effect of Supplementation with Methyl-Donor Nutrients on Neurodevelopment and Cognition: Considerations for Future Research. Nutr. Rev. 2018, 76, 497–511, doi:10.1093/nutrit/nuy007.
Fernandez-Osornio, L.F.; Gomez-Diaz, R.A.; Mondragon-Gonzalez, R.; Gonzalez-Carranza, E.; Diaz-Flores, M.; Sharma, T.; Hernández-Pineda, J.; Maldonado-Rodriguez, R.; Wacher, N.H.; Cruz, M.; et al. Micronutrients of the One-Carbon Metabolism Cycle Are Altered in Mothers and Neonates by Gestational Diabetes and Are Associated with Weight, Height and Head Circumference at Birth. J. Nutr. Biochem. 2022, 105, 108996, doi:10.1016/j.jnutbio.2022.108996.
Naninck, E.F.G.; Stijger, P.C.; Brouwer-Brolsma, E.M. The Importance of Maternal Folate Status for Brain Development and Function of Offspring. Adv. Nutr. 2019, 10, 502–519, doi:10.1093/advances/nmy120.
Stamm, R.A.; Houghton, L.A. Nutrient Intake Values for Folate during Pregnancy and Lactation Vary Widely around the World. Nutrients 2013, 5, 3920–3947, doi:10.3390/nu5103920.
Mehedint, M.G.; Craciunescu, C.N.; Zeisel, S.H. Maternal Dietary Choline Deficiency Alters Angiogenesis in Fetal Mouse Hippocampus. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 12834–12839, doi:10.1073/pnas.0914328107.
Deoni, S.; Dean, D.; Joelson, S.; O’Regan, J.; Schneider, N. Early Nutrition Influences Developmental Myelination and Cognition in Infants and Young Children. NeuroImage 2018, 178, 649–659, doi:10.1016/j.neuroimage.2017.12.056.
Jadavji, N.M.; Deng, L.; Malysheva, O.; Caudill, M.A.; Rozen, R. MTHFR Deficiency or Reduced Intake of Folate or Choline in Pregnant Mice Results in Impaired Short-Term Memory and Increased Apoptosis in the Hippocampus of Wild-Type Offspring. Neuroscience 2015, 300, 1–9, doi:10.1016/j.neuroscience.2015.04.067.
Schlotz, W.; Jones, A.; Phillips, D.I.W.; Gale, C.R.; Robinson, S.M.; Godfrey, K.M. Lower Maternal Folate Status in Early Pregnancy Is Associated with Childhood Hyperactivity and Peer Problems in Offspring. J. Child Psychol. Psychiatry 2010, 51, 594–602, doi:10.1111/j.1469-7610.2009.02182.x.
Breimer, L.H.; Nilsson, T.K. Has Folate a Role in the Developing Nervous System after Birth and Not Just during Embryogenesis and Gestation? Scand. J. Clin. Lab. Invest. 2012, 72, 185–191, doi:10.3109/00365513.2012.657230.
Li, M.; Francis, E.; Hinkle, S.N.; Ajjarapu, A.S.; Zhang, C. Preconception and Prenatal Nutrition and Neurodevelopmental Disorders: A Systematic Review and Meta-Analysis. Nutrients 2019, 11, E1628, doi:10.3390/nu11071628.
Prado, E.L.; Dewey, K.G. Nutrition and Brain Development in Early Life. Nutr. Rev. 2014, 72, 267–284, doi:10.1111/nure.12102.
Antony, A.C. In Utero Physiology: Role of Folic Acid in Nutrient Delivery and Fetal Development. Am. J. Clin. Nutr. 2007, 85, 598S-603S, doi:10.1093/ajcn/85.2.598S.
Craciunescu, C.N.; Brown, E.C.; Mar, M.-H.; Albright, C.D.; Nadeau, M.R.; Zeisel, S.H. Folic Acid Deficiency During Late Gestation Decreases Progenitor Cell Proliferation and Increases Apoptosis in Fetal Mouse Brain. J. Nutr. 2004, 134, 162–166, doi:10.1093/jn/134.1.162.
Akchiche, N.; Bossenmeyer-Pourié, C.; Kerek, R.; Martin, N.; Pourié, G.; Koziel, V.; Helle, D.; Alberto, J.-M.; Ortiou, S.; Camadro, J.-M.; et al. Homocysteinylation of Neuronal Proteins Contributes to Folate Deficiency-Associated Alterations of Differentiation, Vesicular Transport, and Plasticity in Hippocampal Neuronal Cells. FASEB J. 2012, 26, 3980–3992, doi:10.1096/fj.12-205757.
Harlan De Crescenzo, A.; Panoutsopoulos, A.A.; Tat, L.; Schaaf, Z.; Racherla, S.; Henderson, L.; Leung, K.-Y.; Greene, N.D.E.; Green, R.; Zarbalis, K.S. Deficient or Excess Folic Acid Supply During Pregnancy Alter Cortical Neurodevelopment in Mouse Offspring. Cereb. Cortex 2021, 31, 635–649, doi:10.1093/cercor/bhaa248.
Zhao, Y.; Chen, D.; Tang, J.; Zheng, Y.; Qi, J.; Wang, H. Parental Folate Deficiency Induces Birth Defects in Mice Accompanied with Increased de Novo Mutations. Cell Discov. 2022, 8, 1–13, doi:10.1038/s41421-021-00364-0.
FREEDMAN, R.; ROSS, R.G. Prenatal Choline and the Development of Schizophrenia. Shanghai Arch. Psychiatry 2015, 27, 90–102, doi:10.11919/j.issn.1002-0829.215006.
Wang, Y.; Surzenko, N.; Friday, W.B.; Zeisel, S.H. Maternal Dietary Intake of Choline in Mice Regulates Development of the Cerebral Cortex in the Offspring. FASEB J. 2016, 30, 1566–1578, doi:10.1096/fj.15-282426.
Jones, J.P.; H. Meck, W.; Williams, C.L.; Wilson, W.A.; Swartzwelder, H.S. Choline Availability to the Developing Rat Fetus Alters Adult Hippocampal Long-Term Potentiation. Dev. Brain Res. 1999, 118, 159–167, doi:10.1016/S0165-3806(99)00103-0.
Glenn, M.J.; Gibson, E.M.; Kirby, E.D.; Mellott, T.J.; Blusztajn, J.K.; Williams, C.L. Prenatal Choline Availability Modulates Hippocampal Neurogenesis and Neurogenic Responses to Enriching Experiences in Adult Female Rats. Eur. J. Neurosci. 2007, 25, 2473–2482, doi:10.1111/j.1460-9568.2007.05505.x.
Ovbiagele, B.; Goldstein, L.B.; Higashida, R.T.; Howard, V.J.; Johnston, S.C.; Khavjou, O.A.; Lackland, D.T.; Lichtman, J.H.; Mohl, S.; Sacco, R.L.; et al. Forecasting the Future of Stroke in the United States: A Policy Statement From the American Heart Association and American Stroke Association. Stroke 2013, 44, 2361–2375, doi:10.1161/STR.0b013e31829734f2.
Mozaffarian, D.; Benjamin, E.J.; Go, A.S.; Arnett, D.K.; Blaha, M.J.; Cushman, M.; Das, S.R.; de Ferranti, S.; Després, J.-P.; Fullerton, H.J.; et al. Heart Disease and Stroke Statistics—2016 Update. 323.
Persky, R.W.; Turtzo, L.C.; McCullough, L.D. Stroke in Women: Disparities and Outcomes. Curr. Cardiol. Rep. 2010, 12, 6–13, doi:10.1007/s11886-009-0080-2.
the Women Initiative for Stroke in Europe (WISE) group; Cordonnier, C.; Sprigg, N.; Sandset, E.C.; Pavlovic, A.; Sunnerhagen, K.S.; Caso, V.; Christensen, H. Stroke in Women — from Evidence to Inequalities. Nat. Rev. Neurol. 2017, 13, 521–532, doi:10.1038/nrneurol.2017.95.
Macrae, I. Preclinical Stroke Research - Advantages and Disadvantages of the Most Common Rodent Models of Focal Ischaemia: Animal Models of Focal Cerebral Ischaemia. Br. J. Pharmacol. 2011, 164, 1062–1078, doi:10.1111/j.1476-5381.2011.01398.x.
Singh, D.; Wasan, H.; Reeta, K.H. Preclinical Stroke Research and Translational Failure: A Bird’s Eye View on Preventable Variables. Cell. Mol. Neurobiol. 2021, doi:10.1007/s10571-021-01083-6.
Jadavji, N.M.; Emmerson, J.T.; MacFarlane, A.J.; Willmore, W.G.; Smith, P.D. B-Vitamin and Choline Supplementation Increases Neuroplasticity and Recovery after Stroke. Neurobiol. Dis. 2017, 103, 89–100, doi:10.1016/j.nbd.2017.04.001.
Jadavji, N.M.; Farr, T.D.; Lips, J.; Khalil, A.A.; Boehm-Sturm, P.; Foddis, M.; Harms, C.; Füchtemeier, M.; Dirnagl, U. Elevated Levels of Plasma Homocysteine, Deficiencies in Dietary Folic Acid and Uracil-DNA Glycosylase Impair Learning in a Mouse Model of Vascular Cognitive Impairment. Behav. Brain Res. 2015, 283, 215–226, doi:10.1016/j.bbr.2015.01.040.
Dam, K.; Füchtemeier, M.; Farr, T.D.; Boehm-Sturm, P.; Foddis, M.; Dirnagl, U.; Malysheva, O.; Caudill, M.A.; Jadavji, N.M. Increased Homocysteine Levels Impair Reference Memory and Reduce Cortical Levels of Acetylcholine in a Mouse Model of Vascular Cognitive Impairment. Behav. Brain Res. 2017, 321, 201–208, doi:10.1016/j.bbr.2016.12.041.
Jadavji, N.M.; Emmerson, J.T.; Shanmugalingam, U.; MacFarlane, A.J.; Willmore, W.G.; Smith, P.D. A Genetic Deficiency in Folic Acid Metabolism Impairs Recovery after Ischemic Stroke. Exp. Neurol. 2018, 309, 14–22, doi:10.1016/j.expneurol.2018.07.014.
Jadavji, N.M.; Mosnier, H.; Kelly, E.; Lawrence, K.; Cruickshank, S.; Stacey, S.; McCall, A.; Dhatt, S.; Arning, E.; Bottiglieri, T.; et al. One-Carbon Metabolism Supplementation Improves Outcome after Stroke in Aged Male MTHFR-Deficient Mice. Neurobiol. Dis. 2019, 132, 104613, doi:10.1016/j.nbd.2019.104613.
Abato, J.E.; Moftah, M.; Cron, G.O.; Smith, P.D.; Jadavji, N.M. Methylenetetrahydrofolate Reductase Deficiency Alters Cellular Response after Ischemic Stroke in Male Mice. Nutr. Neurosci. 2020, doi:10.1080/1028415X.2020.1769412.
Esfandiarei, M.; Hoxha, B.; Talley, N.A.; Anderson, M.R.; Alkhouli, M.F.; Squire, M.A.; Eckman, D.M.; Babu, J.R.; Lopaschuk, G.D.; Broderick, T.L. Beneficial Effects of Resveratrol and Exercise Training on Cardiac and Aortic Function and Structure in the 3xTg Mouse Model of Alzheimer’s Disease. Drug Des. Devel. Ther. 2019, 13, 1197–1211, doi:10.2147/DDDT.S196119.
Kuechenmeister, B.; Gusek, B.; Jones, T.B.; Esfandiarei, M. Evaluation of the Effects of Marfan Pathogenesis and Losartan Treatment on Coronary and Cerebral Arteries in the Well-Established Marfan Syndrome Mouse Model. FASEB J. 2021, 35, doi:10.1096/fasebj.2021.35.S1.03693.
Purkayastha, S.; Sorond, F. Transcranial Doppler Ultrasound: Technique and Application. Semin. Neurol. 2012, 32, 411–420, doi:10.1055/s-0032-1331812.
Aaslid, R.; Markwalder, T.M.; Nornes, H. Noninvasive Transcranial Doppler Ultrasound Recording of Flow Velocity in Basal Cerebral Arteries. J. Neurosurg. 1982, 57, 769–774, doi:10.3171/jns.1982.57.6.0769.
Whiteus, C.; Freitas, C.; Grutzendler, J. Perturbed Neural Activity Disrupts Cerebral Angiogenesis during a Postnatal Critical Period. Nature 2014, 505, 407–411, doi:10.1038/nature12821.
Peguera, B.; Segarra, M.; Acker-Palmer, A. Neurovascular Crosstalk Coordinates the Central Nervous System Development. Curr. Opin. Neurobiol. 2021, 69, 202–213, doi:10.1016/j.conb.2021.04.005.
Paredes, I.; Himmels, P.; Ruiz de Almodóvar, C. Neurovascular Communication during CNS Development. Dev. Cell 2018, 45, 10–32, doi:10.1016/j.devcel.2018.01.023.
Tata, M.; Ruhrberg, C. Cross-Talk between Blood Vessels and Neural Progenitors in the Developing Brain. Neuronal Signal. 2018, 2, NS20170139, doi:10.1042/NS20170139.
Wang, L.; Xiong, X.; Zhang, L.; Shen, J. Neurovascular Unit: A Critical Role in Ischemic Stroke. CNS Neurosci. Ther. 2021, 27, 7–16, doi:10.1111/cns.13561.
Lecrux, C.; Hamel, E. The Neurovascular Unit in Brain Function and Disease. Acta Physiol. Oxf. Engl. 2011, 203, 47–59, doi:10.1111/j.1748-1716.2011.02256.x.
Guan, J.; Pavlovic, D.; Dalkie, N.; Waldvogel, H.J.; O’Carroll, S.J.; Green, C.R.; Nicholson, L.F.B. Vascular Degeneration in Parkinson’s Disease. Brain Pathol. 2012, 23, 154–164, doi:10.1111/j.1750-3639.2012.00628.x.
Murphy, M.J.; Grace, G.M.; Tartaglia, M.C.; Orange, J.B.; Chen, X.; Rowe, A.; Findlater, K.; Kozak, R.I.; Freedman, M.; Lee, T.-Y.; et al. Widespread Cerebral Haemodynamics Disturbances Occur Early in Amyotrophic Lateral Sclerosis. Amyotroph. Lateral Scler. Off. Publ. World Fed. Neurol. Res. Group Mot. Neuron Dis. 2012, 13, 202–209, doi:10.3109/17482968.2011.625569.
Kisler, K.; Nelson, A.R.; Montagne, A.; Zlokovic, B.V. Cerebral Blood Flow Regulation and Neurovascular Dysfunction in Alzheimer’s Disease. Nat. Rev. Neurosci. 2017, 18, 419–434, doi:10.1038/nrn.2017.48.
Toledo, J.B.; Arnold, S.E.; Raible, K.; Brettschneider, J.; Xie, S.X.; Grossman, M.; Monsell, S.E.; Kukull, W.A.; Trojanowski, J.Q. Contribution of Cerebrovascular Disease in Autopsy Confirmed Neurodegenerative Disease Cases in the National Alzheimer’s Coordinating Centre. Brain 2013, 136, 2697–2706, doi:10.1093/brain/awt188.
Muoio, V.; Persson, P.B.; Sendeski, M.M. The Neurovascular Unit – Concept Review. Acta Physiol. 2014, 210, 790–798, doi:10.1111/apha.12250.
Contu, L.; Nizari, S.; Heath, C.J.; Hawkes, C.A. Pre- and Post-Natal High Fat Feeding Differentially Affects the Structure and Integrity of the Neurovascular Unit of 16-Month Old Male and Female Mice. Front. Neurosci. 2019, 13, 1045, doi:10.3389/fnins.2019.01045.
Bordeleau, M.; Comin, C.H.; Fernández de Cossío, L.; Lacabanne, C.; Freitas-Andrade, M.; González Ibáñez, F.; Raman-Nair, J.; Wakem, M.; Chakravarty, M.; Costa, L. da F.; et al. Maternal High-Fat Diet in Mice Induces Cerebrovascular, Microglial and Long-Term Behavioural Alterations in Offspring. Commun. Biol. 2022, 5, 1–13, doi:10.1038/s42003-021-02947-9.
Bordeleau, M.; Fernández de Cossío, L.; Chakravarty, M.M.; Tremblay, M.-È. From Maternal Diet to Neurodevelopmental Disorders: A Story of Neuroinflammation. Front. Cell. Neurosci. 2021, 14.
Xiong, B.; Li, A.; Lou, Y.; Chen, S.; Long, B.; Peng, J.; Yang, Z.; Xu, T.; Yang, X.; Li, X.; et al. Precise Cerebral Vascular Atlas in Stereotaxic Coordinates of Whole Mouse Brain. Front. Neuroanat. 2017, 11.
Haubrich, C.; Wendt, A.; Diehl, R. r.; Klötzsch, C. Dynamic Autoregulation Testing in the Posterior Cerebral Artery. Stroke 2004, 35, 848–852, doi:10.1161/01.STR.0000120729.99039.B6.
Zeisel, S.H. Nutritional Importance of Choline for Brain Development. J. Am. Coll. Nutr. 2004, 23, 621S-626S, doi:10.1080/07315724.2004.10719433.
Radziejewska, A.; Chmurzynska, A. Folate and Choline Absorption and Uptake: Their Role in Fetal Development. Biochimie 2019, 158, 10–19, doi:10.1016/j.biochi.2018.12.002.
Jiang, X.; Bar, H.Y.; Yan, J.; Jones, S.; Brannon, P.M.; West, A.A.; Perry, C.A.; Ganti, A.; Pressman, E.; Devapatla, S.; et al. A Higher Maternal Choline Intake among Third-Trimester Pregnant Women Lowers Placental and Circulating Concentrations of the Antiangiogenic Factor Fms-like Tyrosine Kinase-1 (SFLT1). FASEB J. 2013, 27, 1245–1253, doi:10.1096/fj.12-221648.
Zhang, L.-C.; Jin, X.; Huang, Z.; Yan, Z.-N.; Li, P.-B.; Duan, R.-F.; Feng, H.; Jiang, J.-H.; Peng, H.; Liu, W. Protective Effects of Choline against Hypoxia-Induced Injuries of Vessels and Endothelial Cells. Exp. Ther. Med. 2017, 13, 2316–2324, doi:10.3892/etm.2017.4276.
Chan, J.; Deng, L.; Mikael, L.G.; Yan, J.; Pickell, L.; Wu, Q.; Caudill, M.A.; Rozen, R. Low Dietary Choline and Low Dietary Riboflavin during Pregnancy Influence Reproductive Outcomes and Heart Development in Mice. Am. J. Clin. Nutr. 2010, 91, 1035–1043, doi:10.3945/ajcn.2009.28754.
Sotres-Alvarez, D.; Siega-Riz, A.M.; Herring, A.H.; Carmichael, S.L.; Feldkamp, M.L.; Hobbs, C.A.; Olshan, A.F.; the National Birth Defects Prevention Study Maternal Dietary Patterns Are Associated With Risk of Neural Tube and Congenital Heart Defects. Am. J. Epidemiol. 2013, 177, 1279–1288, doi:10.1093/aje/kws349.
Golzarand, M.; Mirmiran, P.; Azizi, F. Association between Dietary Choline and Betaine Intake and 10.6-Year Cardiovascular Disease in Adults. Nutr. J. 2022, 21, 1, doi:10.1186/s12937-021-00755-9.
Liu, L.; Lu, Y.; Bi, X.; Xu, M.; Yu, X.; Xue, R.; He, X.; Zang, W. Choline Ameliorates Cardiovascular Damage by Improving Vagal Activity and Inhibiting the Inflammatory Response in Spontaneously Hypertensive Rats. Sci. Rep. 2017, 7, 42553, doi:10.1038/srep42553.
Bohm, M.; Cotton, D.; Foster, L.; Custodis, F.; Laufs, U.; Sacco, R.; Bath, P.M.W.; Yusuf, S.; Diener, H.-C. Impact of Resting Heart Rate on Mortality, Disability and Cognitive Decline in Patients after Ischaemic Stroke. Eur. Heart J. 2012, 33, 2804–2812, doi:10.1093/eurheartj/ehs250.
Custodis, F.; Gertz, K.; Balkaya, M.; Prinz, V.; Mathar, I.; Stamm, C.; Kronenberg, G.; Kazakov, A.; Freichel, M.; Böhm, M.; et al. Heart Rate Contributes to the Vascular Effects of Chronic Mental Stress. Stroke 2011, 42, 1742–1749, doi:10.1161/STROKEAHA.110.598607.
Laufs, U.; Gertz, K.; Dirnagl, U.; Böhm, M.; Nickenig, G.; Endres, M. Rosuvastatin, a New HMG-CoA Reductase Inhibitor, Upregulates Endothelial Nitric Oxide Synthase and Protects from Ischemic Stroke in Mice. Brain Res. 2002, 942, 23–30, doi:10.1016/S0006-8993(02)02649-5.
Bolduc, V.; Drouin, A.; Gillis, M.-A.; Duquette, N.; Thorin-Trescases, N.; Frayne-Robillard, I.; Des Rosiers, C.; Tardif, J.-C.; Thorin, E. Heart Rate-Associated Mechanical Stress Impairs Carotid but Not Cerebral Artery Compliance in Dyslipidemic Atherosclerotic Mice. Am. J. Physiol.-Heart Circ. Physiol. 2011, 301, H2081–H2092, doi:10.1152/ajpheart.00706.2011.
Yabluchanskiy, A.; Nyul-Toth, A.; Csiszar, A.; Gulej, R.; Saunders, D.; Towner, R.; Turner, M.; Zhao, Y.; Abdelkari, D.; Rypma, B.; et al. Age-Related Alterations in the Cerebrovasculature Affect Neurovascular Coupling and BOLD FMRI Responses: Insights from Animal Models of Aging. Psychophysiology 2021, 58, e13718, doi:10.1111/psyp.13718.
Hakim, M.A.; Chum, P.P.; Buchholz, J.N.; Behringer, E.J. Aging Alters Cerebrovascular Endothelial GPCR and K+ Channel Function: Divergent Role of Biological Sex. J. Gerontol. A. Biol. Sci. Med. Sci. 2020, 75, 2064–2073, doi:10.1093/gerona/glz275.
Mandalà, M.; Pedatella, A.L.; Morales Palomares, S.; Cipolla, M.J.; Osol, G. Maturation Is Associated with Changes in Rat Cerebral Artery Structure, Biomechanical Properties and Tone. Acta Physiol. Oxf. Engl. 2012, 205, 363–371, doi:10.1111/j.1748-1716.2011.02406.x.
Caporarello, N.; Meridew, J.A.; Aravamudhan, A.; Jones, D.L.; Austin, S.A.; Pham, T.X.; Haak, A.J.; Moo Choi, K.; Tan, Q.; Haresi, A.; et al. Vascular Dysfunction in Aged Mice Contributes to Persistent Lung Fibrosis. Aging Cell 2020, 19, e13196, doi:10.1111/acel.13196.
Donato, A.J.; Machin, D.R.; Lesniewski, L.A. Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease. Circ. Res. 2018, 123, 825–848, doi:10.1161/CIRCRESAHA.118.312563.
Barros, P.R.; Costa, T.J.; Akamine, E.H.; Tostes, R.C. Vascular Aging in Rodent Models: Contrasting Mechanisms Driving the Female and Male Vascular Senescence. Front. Aging 2021, 2, 727604, doi:10.3389/fragi.2021.727604.
Anderson, H.V.; Stokes, M.J.; Leon, M.; Abu-Halawa, S.A.; Stuart, Y.; Kirkeeide, R.L. Coronary Artery Flow Velocity Is Related To Lumen Area and Regional Left Ventricular Mass. Circulation 2000, 102, 48–54, doi:10.1161/01.CIR.102.1.48.
Global, Regional, and National Incidence, Prevalence, and Years Lived with Disability for 354 Diseases and Injuries for 195 Countries and Territories, 1990–2017: A Systematic Analysis for the Global Burden of Disease Study 2017. Lancet Lond. Engl. 2018, 392, 1789–1858, doi:10.1016/S0140-6736(18)32279-7.
Kosaraju, A.; Goyal, A.; Grigorova, Y.; Makaryus, A.N. Left Ventricular Ejection Fraction. In StatPearls; StatPearls Publishing: Treasure Island (FL), 2022.
Becklake, M.R.; Frank, H.; Dagenais, G.R.; Ostiguy, G.L.; Guzman, C.A. Influence of Age and Sex on Exercise Cardiac Output. J. Appl. Physiol. 1965, 20, 938–947, doi:10.1152/jappl.1965.20.5.938.
McEniery, C.M.; Yasmin; Hall, I.R.; Qasem, A.; Wilkinson, I.B.; Cockcroft, J.R. Normal Vascular Aging: Differential Effects on Wave Reflection and Aortic Pulse Wave Velocity: The Anglo-Cardiff Collaborative Trial (ACCT). J. Am. Coll. Cardiol. 2005, 46, 1753–1760, doi:10.1016/j.jacc.2005.07.037.

No competing interests reported.

SupplementaryData.xlsx

Download PDF

Version 1

posted

You are reading this latest preprint version

Aging and maternal dietary dietary deficiencies during pregnancy and lactation change cerebral and peripheral blood flow in adult female mice offspring following ischemic stroke to the sensorimotor cortex

Status:

Version 1

Abstract

Figures

Introduction

Results

Cerebral blood flow in offspring after ischemic stroke

Cardiac/Aortic (Peripheral) hemodynamics in offspring after ischemic stroke

The impact of aging on cerebral blood flow and cardiac/aortic hemodyamics

Discussion

Materials And Methods

Experimental Design

Photothrombosis

Ultrasound imaging

Statistics

Declarations

Acknowledgments

Conflict of Interest

Data availability statement –

Author Contributions

References

Additional Declarations

Supplementary Files

Status:

Version 1