1,25-Dihydroxyvitamin D3 stimulates vascular smooth muscle cell proliferation through a VEGF-mediated pathway

Abstract

Atherosclerosis is a complex process characterized by an increase in the wall thickness owing to the accumulation of cells and extracellular matrix between the endothelium and the smooth muscle cell wall. This process is associated with different pathologies and it is accelerated in patients with chronic renal failure. In these patients, decreased synthesis of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) leads to secondary complications, like hyperparathyroidism, and treatment with 1,25(OH)(2)D(3) is a common practice. The effect of 1,25(OH)(2)D(3) on vascular smooth muscle cells (VSMCs) calcification has been widely studied, but the role of 1,25(OH)(2)D(3) on VSMC proliferation remains obscure. We have analyzed the effects of 1,25(OH)(2)D(3) in the proliferation of VSMC. We found that 1,25(OH)(2)D(3) (5-100 nM) induces a dose-dependent increase in VSMC proliferation in quiescent cells and in cells stimulated to grow. This increase in proliferation is achieved by shortening the G1 phase. The effect of 1,25(OH)(2)D(3) on VSMC proliferation is mediated by an increase of the expression of vascular endothelial growth factor A (VEGF), as the inhibition of VEGF activity totally blunted the 1,25(OH)(2) D(3)-induced VSMC proliferation. We found this increase in proliferation in vitro, ex vivo in aortic rings incubated with 1,25(OH)(2)D(3), and in vivo in animals with a model of chronic renal failure (5/6 nephrectomy) treated with 1,25(OH)(2)D(3) (1 mug/kg three times a week for 8 weeks). Thus, we conclude that 1,25(OH)(2)D(3) induces increases in VSMC proliferation through an increase on VEGF expression.

The Effects of Vitamin D Deficiency on Atrial Fibrillation

“…Vitamin D directly leads to vitamin D receptor (VDR) and CYP27B1 expressions in the vascular smooth muscle cells and in endothelial cells, it enhances the proliferation of vascular smooth muscle cells and expression of vascular endothelial growth factor within these cells and inhibits the proliferation of cardiomyocytes. 6 Indirect cardioprotective effects of vitamin D are explained by certain mechanisms. Vitamin D ensures blood pressure regulation and prevents cardiac hypertrophy by inhibiting the activation of renin, hinders the formation of vascular calcification by reducing the production of matrix metalloproteinases 2 (MMP2) and MMP9, provides glycemic control, leads to pro inflammatory cytokine suppression and an increase in interleukin (IL)-10 levels, and has cardioprotective effects through hindering secondary hyperparathyroidism.…”

“…Vitamin D ensures blood pressure regulation and prevents cardiac hypertrophy by inhibiting the activation of renin, hinders the formation of vascular calcification by reducing the production of matrix metalloproteinases 2 (MMP2) and MMP9, provides glycemic control, leads to pro inflammatory cytokine suppression and an increase in interleukin (IL)-10 levels, and has cardioprotective effects through hindering secondary hyperparathyroidism. 6 Several mechanisms have been proposed for AF development. One of these mechanisms is the atrial wall tension.…”

“…38 It is known that vitamin D suppresses pro-inflammatory cytokines and causes an increase in IL-10 levels. 6 Because of that effect, it is thought that vitamin D deficiency might be related to the development of and sustaining AF. Transforming growth factor b 1 increases atrial fibrosis under normal atrial action potential and under normal ventricular structure and function.…”

Large Artery Calcification on Dialysis Patients Is Located in the Intima and Related to Atherosclerosis

“…VC has been historically classified as (1) intima calcification associated with atheroma plaques and (2) medial calcification mediated by a switch of vascular smooth muscle cells (VSMCs) to a procalcification phenotype and associated with CKD and disturbances in the metabolism of calcium, phosphorus, and vitamin D (19). However several potential flaws associated with this traditional view and the data on which it is based have to be considered.…”

Vitamin D, Blood Pressure, and African Americans

“…It has been shown to mediate endothelium-dependent vasodilation by increasing expression of vascular endothelial growth factor that can upregulate endothelial nitric oxide synthase and also stimulate VSMC proliferation (25). 1,25(OH)2D3 also produces VSMC vasodilation by stimulation of prostacyclin production (26) and by reducing endothelium-dependent VSMC contractions by reducing influx of calcium into endothelial cells (27).…”