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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2015     Display Documents



ID: 711842.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
Vitamin D promotes vascular regeneration
Authors:Wong, M. S.; Leisegang, M. S.; Kruse, C.; Vogel, J.; Schurmann, C.; Dehne, N.; Weigert, A.; Herrmann, E.; Brune, B.; Shah, A. M.; Steinhilber, D.; Offermanns, S.; Carmeliet, G.; Badenhoop, K.; Schroder, K.; Brandes, R. P.
Date of Publication (YYYY-MM-DD):2014-09-16
Title of Journal:Circulation
Volume:130
Issue / Number:12
Start Page:976
End Page:986
Audience:Not Specified
Abstract / Description: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-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 D3 is a novel approach to promote vascular repair.
Free Keywords:Adult; Animals; Calcitriol/*pharmacology; Chemokine CXCL12/physiology; Endothelium, Vascular/drug effects/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
External Publication Status:published
Document Type:Article
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations: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 fur 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. %^ 1435822116
Identifiers:ISSN:1524-4539 (Electronic) 0009-7322 (Linking) %R 10.1161/CIRCULATIONAHA.114.010650
URL:http://www.ncbi.nlm.nih.gov/pubmed/25015343
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