title: Elimination of vitamin D receptor in vascular endothelial cells alters vascular function.
abstract: Vitamin D deficiency has been associated with cardiovascular dysfunction. We evaluated the role of the vitamin D receptor (VDR) in vascular endothelial function, a marker of cardiovascular health, at baseline and in the presence of angiotensin II, using an endothelial-specific knockout of the murine VDR gene. In the absence of endothelial VDR, acetylcholine-induced aortic relaxation was significantly impaired (maximal relaxation, endothelial-specific VDR knockout=58% versus control=73%; P<0.05). This was accompanied by a reduction in endothelial NO synthase expression and phospho-vasodilator-stimulated phosphoprotein levels in aortae from the endothelial-specific VDR knockout versus control mice. Although blood pressure levels at baseline were comparable at 12 and 24 weeks of age, the endothelial VDR knockout mice demonstrated increased sensitivity to the hypertensive effects of angiotensin II compared with control mice (after 1-week infusion: knockout=155±15 mm Hg versus control=133±7 mm Hg; P<0.01; after 2-week infusion: knockout=164±9 mm Hg versus control=152±13 mm Hg; P<0.05). By the end of 2 weeks, angiotensin II infusion-induced, hypertrophy-sensitive myocardial gene expression was higher in endothelial-specific VDR knockout mice (fold change compared with saline-infused control mice, type-A natriuretic peptide: knockout mice=3.12 versus control=1.7; P<0.05; type-B natriuretic peptide: knockout mice=4.72 versus control=2.68; P<0.05). These results suggest that endothelial VDR plays an important role in endothelial cell function and blood pressure control and imply a potential role for VDR agonists in the management of cardiovascular disease associated with endothelial dysfunction.
authors.affiliation: From the Department of Medicine and Diabetes Center, University of California at San Francisco (W.N., M.N., S.C., D.J.G. and D.G.G); and the Department of Pharmacology and Toxicology, Michigan State University, East Lansing (S.W.W.). niwei78@gmail.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Ni
authors.affiliation: From the Department of Medicine and Diabetes Center, University of California at San Francisco (W.N., M.N., S.C., D.J.G. and D.G.G); and the Department of Pharmacology and Toxicology, Michigan State University, East Lansing (S.W.W.).
authors.forename: Stephanie W
authors.initials: SW
authors.lastname: Watts
authors.affiliation: From the Department of Medicine and Diabetes Center, University of California at San Francisco (W.N., M.N., S.C., D.J.G. and D.G.G); and the Department of Pharmacology and Toxicology, Michigan State University, East Lansing (S.W.W.).
authors.forename: Michael
authors.initials: M
authors.lastname: Ng
authors.affiliation: From the Department of Medicine and Diabetes Center, University of California at San Francisco (W.N., M.N., S.C., D.J.G. and D.G.G); and the Department of Pharmacology and Toxicology, Michigan State University, East Lansing (S.W.W.).
authors.forename: Songcang
authors.initials: S
authors.lastname: Chen
authors.affiliation: From the Department of Medicine and Diabetes Center, University of California at San Francisco (W.N., M.N., S.C., D.J.G. and D.G.G); and the Department of Pharmacology and Toxicology, Michigan State University, East Lansing (S.W.W.).
authors.forename: Denis J
authors.initials: DJ
authors.lastname: Glenn
authors.affiliation: From the Department of Medicine and Diabetes Center, University of California at San Francisco (W.N., M.N., S.C., D.J.G. and D.G.G); and the Department of Pharmacology and Toxicology, Michigan State University, East Lansing (S.W.W.).
authors.forename: David G
authors.initials: DG
authors.lastname: Gardner
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D051381:Rats; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D018167:Receptors, Calcitriol; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D004247:DNA; D000109:Acetylcholine
keywords: gene targeting; hypertension; receptors, calcitriol; vitamin D