Vitamin D Promotes Vascular Regeneration
Background—Vitamin D deficiency in humans is frequent and has been associated with inflammation. The role of the active hormone, 1,25-dihydroxy-vitamin D3 (1,25-VitD3) in the cardiovascular system is controversial. High doses induce vascular calcification; vitamin D3 deficiency, however, has been linked to cardiovascular disease as the hormone has anti-inflammatory properties. We therefore hypothesized that 1,25-VitD3 promotes regeneration after vascular injury.
Methods and Results—In healthy volunteers supplementation of VitD3 (4000 I.E. cholecalciferol/day) increased the number of circulating CD45-CD117+Sca1+Flk1+ angiogenic myeloid cells (AMC), which are thought to promote vascular regeneration. Similarly, in mice 1,25-VitD3 (100ng/kg/d) increased the number of AMCs and promoted re-endothelialization in the carotid artery injury model. In streptozotocin-diabetic mice, 1,25-VitD3 also promoted reendothelialization and restored the impaired angiogenesis in the femoral artery ligation model. AMCs home through the stromal cell-derived factor 1 (SDF1) receptor CXCR4. Inhibition of CXCR4 blocked 1,25-VitD3-stimulated healing pointing to a role of SDF1. The combination of injury and 1,25-VitD3 increased SDF1 in vessels. Conditioned medium from injured, 1,25-VitD3 treated arteries elicited a chemotactic effect on AMCs, which was blocked by SDF1-neutralizing antibodies. Conditional knockout of the vitamin D receptor (VDR) in myeloid cells but not the endothelium or smooth muscle cells blocked the effects of 1,25-VitD3 on healing and prevented SDF1 formation. Mechanistically, 1,25-VitD3 increased Hif1α through binding to its promoter. Increased HIF signaling subsequently promoted SDF1 expression as revealed by reporter assays and knockout and inhibitory strategies of HIF1α.
Conclusions—By inducing SDF1, VitD3 is a novel approach to promote vascular repair.
- Received April 16, 2014.
- Revision received June 11, 2014.
- Accepted July 7, 2014.