Vitamin D Promotes Vascular Regeneration

Abstract

V itamin D is a misnomer. The body produces this hormone through precursors with final hydroxylation to the most active metabolite 1, 1,. Vitamin D is ingested with food or synthesized from the precursor 7-dehydrocholesterol, which is then photochemically converted in the sunlight-exposed skin into cholecalciferol (vitamin D 3 ). Active 1,25-VitD3 is generated by 2 hydroxylation steps: 25β-hydroxylation in the liver followed by 1α-hydroxylation in the kidney. The latter reaction is particularly rate limiting, and thus the effective concentration of 1,25-VitD3 is much lower than that of vitamin D 3 or 25-hydroxy-vitamin D 3 . By a positive feedback loop, 1,25-VitD3 induces 24-hydroxylase expression. Because 1,24, is water soluble and cleared by the kidney, this pathway limits the effects of the hormone, and 24-hydroxylase expression can be used as a marker for the biological activity of 1,25-VitD3. Unless vitamin D is supplemented, intake with food is usually insufficient, and thus endogenous production contributes significantly to plasma levels. This leads to vitamin D deficiencies in up to 70% in some population groups in which sunlight exposure is low because of modern lifestyle, clothing, and few sunshine hours during winter. 1,2 Clinical Perspective on p 986Background-Vitamin D deficiency in humans is frequent and has been associated with inflammation. The role of the active hormone 1, 1, 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-α through binding to its promoter. Increased hypoxia-inducible factor signaling subsequently...

Pleiotropic Effects of Vitamin D in Kidney Disease

“…Vitamin D therapy can improve endothelial function. Oral vitamin D (cholecalciferol) improves endothelial vasomotor and secretory functions in CKD patients [62,63]. In a clinical trial of patients with type 2 DM, who were vitamin D deficient, a one-time large dose of vitamin D improved flow-mediated brachial artery vasodilation and significantly decreased systolic BP compared with placebo [64].…”

Bone Metabolism Markers in Aortic Stenosis and the Role of Vitamin D Deficiency

“…Известно, что вита-мин D влияет на иммунные процессы, предотвращая чрезмерную экспрессию воспалительных цитокинов и повышение окислительного потенциала макрофа-гов [8]. В экспериментальных работах продемонстри-рован противовоспалительный эффект витамина D, в частности, в отношении эндотелиальной дисфунк-ции и регенерации сосудистой стенки [19,22]. Воз-можно, данный эффект имеет значение и при разви-тии АС.…”

Physiological functions of vitamin D: what we have learned from global and conditional VDR knockout mouse studies

“…Besides the critical role of 1a,25(OH) 2 D 3 through VDR in intestinal calcium transport, additional important functions of VDR action have been defined at other target tissues of vitamin D (Table 1). To date, specific 1a,25(OH) 2 D 3 activities have been demonstrated by the genetic manipulation of VDR in several tissues and cells such as chondrocytes [42], parathyroid glands [43], cardiomyocytes [44], intestine [24 ], osteocytes [24 ], and osteoblasts [45 ] as well as in monocytic cells [46]. Tissue-specific VDR overexpression restoring 1a,25(OH) 2 D 3 function has also been assessed as a counter part of conditional VDR KO mice.…”