Beneficial Role of Vitamin D on Endothelial Progenitor Cells (EPCs) in Cardiovascular Diseases

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death in the world. Endothelial progenitor cells (EPCs) are currently being explored in the context of CVD risk. EPCs are bone marrow derived progenitor cells involved in postnatal endothelial repair and neovascularization. A large body of evidence from clinical, animal, and in vitro studies have shown that EPC numbers in circulation and their functionality reflect endogenous vascular regenerative capacity. Traditionally vitamin D is known to be beneficial for bone health and calcium metabolism and in the last two decades, its role in influencing CVD and cancer risk has generated significant interest. Observational studies have shown that low vitamin D levels are associated with an adverse cardiovascular risk profile. Still, Mendelian randomization studies and randomized control trials (RCTs) have not shown significant effects of vitamin D on cardiovascular events. The criticism regarding the RCTs on vitamin D and CVD is that they were not designed to investigate cardiovascular outcomes in vitamin D-deficient individuals. Overall, the association between vitamin D and CVD remains inconclusive. Recent clinical and experimental studies have demonstrated the beneficial role of vitamin D in increasing the circulatory level of EPC as well as their functionality. In this review we present evidence supporting the beneficial role of vitamin D in CVD through its modulation of EPC homeostasis.

Keywords: Cardiovascular diseases; Endothelial progenitor cell; Vitamin D.

Fig. 1. Bright field microscopic images of early (A) and late (B) EPCs with spindle shape and typical cobble stone morphology. Both the images are at 10× magnification with 100 µm scale bar.

Fig. 2. Schematic representation of effect of vitamin D3 on EPCs and/or endothelial cells. Binding of vitamin D to nuclear VDR in combination with RXR on VDRE triggers the expression of number of genes, such as eNOS, VEGF, CuZn dismutase, and pro-autophagic bacilin-1. Vitamin D3 mediates activation of eNOS by phosphorylation resulting in the augmentation of NO synthesis. Intracellular Ca²⁺ influx is caused by vitamin D and subsequent calcium calmodulin complex stabilizes the catalytic state of eNOS which catalyzes the synthesis of NO from L-Arginine and molecular oxygen. In association with VEGF, SDF-1 and MMP-9, NO leads to the migration of EPC from the permissive vascular zone of bone marrow into the circulation. The upregulation of CuZn dismutase by vitamin D3 via VDR activation attenuates the cellular oxidative stress, while upregulation of pro-autophagic bacilin-1 by VDR mediated vitamin D3 reduces the cellular apoptosis. Increased VEGF mRNA expression and protein synthesis mediates EPC migration, proliferation, and in vitro angiogenesis. Upregulation of microRNA (miR-659, miR-510) and downregulation of microRNA (miR-181c, miR-411, miR-126, miR-15a, miR-20b) seen in hyperglycemic conditions like diabetes are reverted by vitamin D3 via VDR signaling pathway. The adhesion of leukocyte and platelets to the endothelium is suppressed by vitamin D3 through downregulation of VCAM-1 and ICAM-1 expression as well as proinflammatory cytokine IL-6. This illustration was created using BioRender.com.

EPC, endothelial progenitor cell; VDR, vitamin D receptor; RXR, retinoid X receptor; VDRE, vitamin D response element; eNOS, endothelial nitric oxide synthase; VEGF, vascular endothelial growth factor; NO, nitric oxide; SDF, stromal derived factor; MMP, matrix metalloproteinase; VCAM-1, vascular cell adhesion molecule-1; ICAM-1, intercellular adhesion molecule-1; IL, interleukin.