Michael Sze Ka Wong1, Matthias S Leisegang1, Christoph Kruse1, Juri Vogel1, Christoph Schürmann1, Nathalie Dehne1, Andreas Weigert1, Eva Herrmann1, Bernhard Brüne1, Ajay M Shah1, Dieter Steinhilber1, Stefan Offermanns1, Geert Carmeliet1, Klaus Badenhoop1, Katrin Schröder2, Ralf P Brandes2. 1. From the Institute for Cardiovascular Physiology (M.S.K.W., M.S.L., C.K., J.V., C.S., K.S., R.P.B.), Institute of Biochemistry I (N.D., A.W., B.B.), Institute for Biostatistics and Mathematical Modeling (E.H.), Institute of Pharmaceutical Chemistry/Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit (D.S.), Goethe University, Frankfurt, Germany; German Center for Cardiovascular Research, Partner Site RheinMain, Frankfurt, Germany (M.S.L., C.K., C.S., E.H., S.O., K.S., R.P.B.); Cardiovascular Division, King's College London British Heart Foundation Center of Excellence, London, United Kingdom (A.M.S.); Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.); Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium (G.C.); and Department of Endocrinology and Diabetes, Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany (K.B.). 2. From the Institute for Cardiovascular Physiology (M.S.K.W., M.S.L., C.K., J.V., C.S., K.S., R.P.B.), Institute of Biochemistry I (N.D., A.W., B.B.), Institute for Biostatistics and Mathematical Modeling (E.H.), Institute of Pharmaceutical Chemistry/Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit (D.S.), Goethe University, Frankfurt, Germany; German Center for Cardiovascular Research, Partner Site RheinMain, Frankfurt, Germany (M.S.L., C.K., C.S., E.H., S.O., K.S., R.P.B.); Cardiovascular Division, King's College London British Heart Foundation Center of Excellence, London, United Kingdom (A.M.S.); Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.O.); Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium (G.C.); and Department of Endocrinology and Diabetes, Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany (K.B.). R.Brandes@em.uni-frankfurt.de Schroeder@vrc.uni-frankfurt.de.
Abstract
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.
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.
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