Vitamin D promotes vascular regeneration

Circulation. 2014 Sep 16;130(12):976-86. doi: 10.1161/CIRCULATIONAHA.114.010650. Epub 2014 Jul 11.


Background: Vitamin D deficiency in humans is frequent and has been associated with inflammation. The role of the active hormone 1,25-dihydroxycholecalciferol (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 because 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 vitamin D3 (4000 IU cholecalciferol per day) increased the number of circulating CD45-CD117+Sca1+Flk1+ angiogenic myeloid cells, which are thought to promote vascular regeneration. Similarly, in mice, 1,25-VitD3 (100 ng/kg per day) increased the number of angiogenic myeloid cells and promoted reendothelialization in the carotid artery injury model. In streptozotocin-induced diabetic mice, 1,25-VitD3 also promoted reendothelialization and restored the impaired angiogenesis in the femoral artery ligation model. Angiogenic myeloid cells 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 angiogenic myeloid cells, which was blocked by SDF1-neutralizing antibodies. Conditional knockout of the vitamin D receptor 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 hypoxia-inducible factor 1-α through binding to its promoter. Increased hypoxia-inducible factor signaling subsequently promoted SDF1 expression, as revealed by reporter assays and knockout and inhibitory strategies of hypoxia-inducible factor 1-α.

Conclusions: By inducing SDF1, vitamin D3 is a novel approach to promote vascular repair.

Keywords: angiogenesis; endothelium; reendothelialization; regeneration; vitamin D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Calcitriol / pharmacology*
  • Chemokine CXCL12 / physiology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiology
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology
  • Male
  • Mice
  • Myeloid Cells / drug effects
  • Neovascularization, Physiologic / drug effects*
  • Receptors, CXCR4 / physiology
  • Regeneration / drug effects*


  • CXCL12 protein, human
  • Chemokine CXCL12
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptors, CXCR4
  • Calcitriol