title: Vitamin D promotes vascular regeneration.
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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Michael Sze Ka
authors.initials: MS
authors.lastname: Wong
authors.affiliation: 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.).
authors.forename: Matthias S
authors.initials: MS
authors.lastname: Leisegang
authors.affiliation: 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.).
authors.forename: Christoph
authors.initials: C
authors.lastname: Kruse
authors.affiliation: 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.).
authors.forename: Juri
authors.initials: J
authors.lastname: Vogel
authors.affiliation: 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.).
authors.forename: Christoph
authors.initials: C
authors.lastname: Schürmann
authors.affiliation: 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.).
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dehne
authors.affiliation: 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.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Weigert
authors.affiliation: 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.).
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
authors.affiliation: 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.).
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
authors.affiliation: 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.).
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.affiliation: 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.).
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.affiliation: 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.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: 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.).
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet
authors.affiliation: 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.).
authors.forename: Klaus
authors.initials: K
authors.lastname: Badenhoop
authors.affiliation: 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.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schröder
authors.affiliation: 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.
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
mesh_terms: D000328:Adult; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D054377:Chemokine CXCL12 / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019718:Receptors, CXCR4 / Q000502:physiology; D012038:Regeneration / Q000187:drug effects*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019718:Receptors, CXCR4; D002117:Calcitriol
keywords: angiogenesis; endothelium; reendothelialization; regeneration; vitamin D