title: The NADPH Oxidase Nox2 Mediates Vitamin D-Induced Vascular Regeneration in Male Mice.
abstract: 1α,25-dihydroxy-vitamin D3 (1,25D) exerts protective effects in the vascular system and promotes myeloid cell differentiation, which are important sources of reactive oxygen species. Given that myeloid cell reactive oxygen species derives from Nox-family NADPH oxidases, we hypothesized that this enzyme family contributes to the beneficial effects of 1,25D on vascular regeneration. The function of Nox enzymes in this context was studied in the murine carotid artery electric injury regeneration model. Male mice were treated with daily injections of 1,25D (100 ng/kg · d) for 5 days and carotid injury was induced after 3 days. After injury, 1,25D increased the expression of Nox2 in the carotid artery. As determined by Evans blue staining on day 6, 1,25D improved vascular regeneration in a Nox2-dependent manner. Healing was lost in mice knockout for Nox2, but not in Nox1 or Nox4, knockout mice. Tissue specific knockouts demonstrated that the myeloid, but not the endothelial Nox2, was required for this effect. Mechanistically, the combination of injury and 1,25D induced the mobilization of angiogenic myeloid cells (AMCs) and increased the vascular expression of the cytokine stem cell derived factor (SDF)1, which attracts AMCs to the site of injury. Vitamin D in a Nox2-dependent manner activated MAPKs, and these are known to contribute to SDF1 induction. Accordingly, SDF1 induction was lost after deletion of Nox2. By inducing SDF1 and enhancing the number of AMCs, VitD3 is a novel approach to promote vascular repair.
authors.affiliation: Institute for Cardiovascular Physiology (M.S.L., A.B., M.S.K.W., V.H., R.P.B., K.S.), Goethe-University, Frankfurt, 60590 Germany; Cancer Research Institute BMC SAS (A.B.), Bratislava, 845 05 Slovakia; and Justus-Liebig Universität Giessen (N.W.), Giessen, 35392 Germany.
authors.forename: Matthias S
authors.initials: MS
authors.lastname: Leisegang
authors.affiliation: Institute for Cardiovascular Physiology (M.S.L., A.B., M.S.K.W., V.H., R.P.B., K.S.), Goethe-University, Frankfurt, 60590 Germany; Cancer Research Institute BMC SAS (A.B.), Bratislava, 845 05 Slovakia; and Justus-Liebig Universität Giessen (N.W.), Giessen, 35392 Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Babelova
authors.affiliation: Institute for Cardiovascular Physiology (M.S.L., A.B., M.S.K.W., V.H., R.P.B., K.S.), Goethe-University, Frankfurt, 60590 Germany; Cancer Research Institute BMC SAS (A.B.), Bratislava, 845 05 Slovakia; and Justus-Liebig Universität Giessen (N.W.), Giessen, 35392 Germany.
authors.forename: Michael Sze Ka
authors.initials: MS
authors.lastname: Wong
authors.affiliation: Institute for Cardiovascular Physiology (M.S.L., A.B., M.S.K.W., V.H., R.P.B., K.S.), Goethe-University, Frankfurt, 60590 Germany; Cancer Research Institute BMC SAS (A.B.), Bratislava, 845 05 Slovakia; and Justus-Liebig Universität Giessen (N.W.), Giessen, 35392 Germany.
authors.forename: Valeska
authors.initials: V
authors.lastname: Helfinger
authors.affiliation: Institute for Cardiovascular Physiology (M.S.L., A.B., M.S.K.W., V.H., R.P.B., K.S.), Goethe-University, Frankfurt, 60590 Germany; Cancer Research Institute BMC SAS (A.B.), Bratislava, 845 05 Slovakia; and Justus-Liebig Universität Giessen (N.W.), Giessen, 35392 Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Weißmann
authors.affiliation: Institute for Cardiovascular Physiology (M.S.L., A.B., M.S.K.W., V.H., R.P.B., K.S.), Goethe-University, Frankfurt, 60590 Germany; Cancer Research Institute BMC SAS (A.B.), Bratislava, 845 05 Slovakia; and Justus-Liebig Universität Giessen (N.W.), Giessen, 35392 Germany.
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
authors.affiliation: Institute for Cardiovascular Physiology (M.S.L., A.B., M.S.K.W., V.H., R.P.B., K.S.), Goethe-University, Frankfurt, 60590 Germany; Cancer Research Institute BMC SAS (A.B.), Bratislava, 845 05 Slovakia; and Justus-Liebig Universität Giessen (N.W.), Giessen, 35392 Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schröder
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000494:pharmacology / Q000627:therapeutic use*; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000201:enzymology; D054377:Chemokine CXCL12 / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects*; D066253:Vascular Remodeling
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D002117:Calcitriol