Abstract 536: Myeloid Nox2 Mediates Vitamin D-induced Vascular Healing
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 whereas deficiency has been linked to cardiovascular disease. We hypothesized that treatment with 1,25-VitD3 promotes vascular regeneration.
Methods and Results: The effects of 1,25-VitD3 in mice and of its precursor, VitD3, in healthy volunteers were studied. In mice, a 1,25-VitD3 (100ng/kg/d) enhanced carotid artery reendothelialization and increased the number of circulating CD45-CD117+Sca1+Flk1+ angiogenic myeloid cells (AMC). Importantly, in streptozotocin-diabetic mice, 1,25-VitD3 also promoted reendothelialization and restored the massively impaired angiogenesis in the femoral artery ligation model. As revealed my conditional knockout mice of the vitamin D receptor (VDR), 1,25-VitD3 increased the production of SDF1 in myeloid, but not endothelial or smooth muscle cells, which then promoted healing and attracted AMCs. This pathway was dependent on Nox2: 1,25-VitD3-induced healing was not affected by genetic deletion of Nox1 or Nox4 but absent in Nox2 knockout mice. Moreover, Nox2 but not Nox1 or Nox4 was induced in the course of healing. 1,25-VitD3 also increased the ROS formation of AMCs as determined by Amplex red / HRP assay. Conditional Nox2 knockout revealed that the effect of 1,25-VitD3 on healing and SDF1 production was mediated by LysM-positive cells but not through the endothelium. Accordingly, in cultured monocytes, stimulation with the combination of cytokines and vitamin D3 increased SDF1 production and this effect was blocked after knockdown of Nox2 or inhibition of the enzyme by gp91-ds-TAT. To determine the clinical relevance of this finding, healthy volunteers were treated with VitD3 (4000 I.E. cholecalciferol/day). Similarly as in mice, also in humans, VitD3 increased the number of circulating AMCs.
Conclusions: By inducing SDF1 and enhancing AMCs, VitD3 through a pathway involving Nox2 is a novel approach to promote vascular repair.
Author Disclosures: K. Schröder: None. S. Wong: None. M. Leisegang: None. A. Shah: None. R. Brandes: None.
- © 2014 by American Heart Association, Inc.