Vascular disorders are the main cause of myocardial infarction, renal failure, blindness, and impaired wound healing in diabetes. These complications raised from progressive disorders in small, medium, and large arteries, increase the risk of peripheral ischemia. Normal tissue reaction to restore its function and minimize ischemic injury is the formation of new vessels from large arteries. Still, diabetic wound healing and myocardial complications are exceptions from the rule(1). However, firm evidence suggests that angiogenesis is affected by a counterbalance between angiogenic and anti-angiogenic stimuli, which may be influenced by a variety of herbal or synthetic drugs used by diabetic patients.
Increased oxygen consumption due to a shift toward fatty acid utilization and also the production of reactive oxygen species (ROS) associates with a decrease in cellular oxygen availability and hypoxia (2). Hypoxia and ROS are the main stimulators of hypoxia-inducible factors (HIFs) by influence on HIF-1α subunit stability. In normoxia, prolyl hydroxylase hydroxylates HIF-1α and causes it to be degraded rapidly, whereas hypoxia and ROS block this process (3, 4). Stabilized HIF-1α bond to HIF-1β activates transcription of several genes for adaptation to hypoxia and ischemia, including pyruvate dehydrogenase kinase 1 to maintain anaerobic glycolysis, VEGF and VEGF receptor to promote angiogenesis and other adaptive processes to accurate tissue alterations. In addition to hypoxia and ROS, HIF-1α expression can be induced by numerous other factors, including nitric oxide (NO), inflammatory cytokines such as TNF-α, pro-inflammatory factors such as hormone-like growth factors such as TGF-β (5). As reported by some researches (6, 7), HIF-1α expression may also be reduced by FGF21, a multifunctional factor with the protective effects on diabetic complications and energy hemostasis (8). VEGF is also up-regulated upon stimulation of such factors. The persistent elevation of HIF-1α level in diabetes and overexpression of VEGF involved in abnormal angiogenesis may cause tissue injuries such as renal failure and some ocular diseases. Despite this phenomenon, a reduction in the expression of myocardial HIF-1α and VEGF exists during diabetic cardiomyopathy, which decreases the capillary density, increases fibrosis, and lowers contractility. Also, studies on excisional skin wounds and fibroblasts of db/db mice showed a marked reduction in HIF-1α expression and Akt/HIF-1α axis activity (5, 9). The crucial effect of VEGF on vascular remodeling and collateral formation, are mediated by binding to its receptors, particularly FLT-1 and FLK-1 which are upregulated via HIF-1α. This binding is typically prevented by the natural circulating form of FLT-1 (sFLT-1). sFLT-1 is another spliced variant of FLT-1 that acts as a VEGF antagonist and a potent inhibitor of angiogenesis. Therefore, altered plasma levels of VEGF and sFLT-1 may be linked to the severity of diabetic vascular complications. It has been demonstrated that the FLT-1 receptor is essential in endothelial cell-cell or cell-matrix interactions, while the FLK-1 receptor regulates differentiating endothelial cells and mitogenesis(10).
Plant phenolic or polyphenolic compounds as natural secondary metabolites have been considered by researchers due to their medicinal properties including antioxidant, anti-inflammatory, antimicrobial, pro/anti-angiogenic, antidiabetic, cardioprotective, hepatoprotective and neuroprotective activities (11, 12). Polyphenolics divided into flavonoids and non-flavonoids are benzene derivatives with carboxylic, hydroxyl, and/or methoxyl groups (13). Several studies have demonstrated both anti- and proangiogenic properties of such phytochemicals with the possible effects on involved factors such as VEGF, HIF-1α, FGF21, TGF, and inflammatory factors (13-15).
Securigera securidaca (L.) Degen & Dorfl (S. securidaca), with local names of Adasol-molk and Bitter-lentils, belongs to the Fabaceae family. The seed of the plant is used in Iranian folk medicine and also by Egyptians and Indians since ancient times to treat several ailments such as diabetes, hyperlipidemia, and hypertension (8, 16, 17). In a chain study, we examine the positive or negative side effects of S. securidaca on diabetes complications. Our previous experiment showed that the herbal extract as a supplement could improve the hypoglycemic, antioxidant, and anti-inflammatory properties of the standard drug (8). In this short report, the possible effect of S. securidaca seeds on neovascularization was evaluated in the diabetic animal model, alone and in combination with glibenclamide.