Vitamin D Promotes Vascular Regeneration
Vitamin D Promotes Vascular Regeneration
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DOI：
10.1161/circulationaha.114.010650
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发表时间：
2014-09-16
期刊：
影响因子：
37.8
通讯作者：
Brandes, Ralf P.
中科院分区：
文献类型：
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作者：
Wong, Michael Sze Ka;Leisegang, Matthias S.;Brandes, Ralf P.
背景-维生素D缺乏症在人类中是常见的，并与炎症有关。活性激素1，25-二羟基胆钙化醇（1，25-dihydroxy-vitamin D-3; 1，25-VitD 3）在心血管系统中的作用是有争议的。高剂量会导致血管钙化;然而，维生素D-3缺乏与心血管疾病有关，因为这种激素具有抗炎特性。因此，我们假设，1，25-VitD 3促进血管injure.Methods和结果再生后，在健康志愿者中，维生素D-3（4000 IU胆钙化醇每天）的补充增加了循环CD 45-CD 117 + Sca 1 + Flk 1+血管生成骨髓细胞，这被认为是促进血管再生的数量。同样，在小鼠中，1，25-VitD 3（100 ng/kg/天）增加了血管生成骨髓细胞的数量，并促进颈动脉损伤模型中的再内皮化。在链脲佐菌素诱导的糖尿病小鼠中，1，25-VitD 3也促进股动脉结扎模型中的再内皮化和恢复受损的血管生成。血管生成性骨髓细胞通过基质细胞衍生因子1（SDF 1）受体CXCR 4归巢。CXCR 4的抑制阻断了1，25-VitD 3刺激的愈合，指出了SDF 1的作用。损伤和1，25-VitD_3的联合作用使血管内SDF_1增加。从受伤的条件培养基，1，25-维生素D3处理的动脉引起的趋化作用的血管生成的髓样细胞，这是由SDF 1的中和抗体阻断。条件性敲除骨髓细胞中的维生素D受体，而不是内皮细胞或平滑肌细胞，阻断了1，25-VitD 3对愈合的影响，并阻止了SDF 1的形成。机制上，1，25-VitD 3通过与其启动子结合而增加缺氧诱导因子1-α。增加缺氧诱导因子信号随后促进SDF 1的表达，揭示了由报告分析和敲除和抑制策略的缺氧诱导因子1-alpha.Conclusions-By诱导SDF 1，维生素D-3是一种新的方法，以促进血管修复。
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 D-3; 1,25-VitD3) in the cardiovascular system is controversial. High doses induce vascular calcification; vitamin D-3 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 D-3 (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-alpha 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-alpha.Conclusions-By inducing SDF1, vitamin D-3 is a novel approach to promote vascular repair.