title: Vitamin D is a regulator of endothelial nitric oxide synthase and arterial stiffness in mice.
abstract: The vitamin D hormone 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] is essential for the preservation of serum calcium and phosphate levels but may also be important for the regulation of cardiovascular function. Epidemiological data in humans have shown that vitamin D insufficiency is associated with hypertension, left ventricular hypertrophy, increased arterial stiffness, and endothelial dysfunction in normal subjects and in patients with chronic kidney disease and type 2 diabetes. However, the pathophysiological mechanisms underlying these associations remain largely unexplained. In this study, we aimed to decipher the mechanisms by which 1,25(OH)2D3 may regulate systemic vascular tone and cardiac function, using mice carrying a mutant, functionally inactive vitamin D receptor (VDR). To normalize calcium homeostasis in VDR mutant mice, we fed the mice lifelong with the so-called rescue diet enriched with calcium, phosphate, and lactose. Here, we report that VDR mutant mice are characterized by lower bioavailability of the vasodilator nitric oxide (NO) due to reduced expression of the key NO synthesizing enzyme, endothelial NO synthase, leading to endothelial dysfunction, increased arterial stiffness, increased aortic impedance, structural remodeling of the aorta, and impaired systolic and diastolic heart function at later ages, independent of changes in the renin-angiotensin system. We further demonstrate that 1,25(OH)2D3 is a direct transcriptional regulator of endothelial NO synthase. Our data demonstrate the importance of intact VDR signaling in the preservation of vascular function and may provide a mechanistic explanation for epidemiological data in humans showing that vitamin D insufficiency is associated with hypertension and endothelial dysfunction.
authors.affiliation: Department of Biomedical Research (O.A., S.S., U.Z., M.S.H., R.G.E.) and Department for Companion Animals and Horses (S.C.R., T.D.A., M.M.), University of Veterinary Medicine Vienna, 1210 Vienna, Austria; and Institute for Surgical Research (W.M.K.), Ludwig Maximilians University, 80539 Munich, Germany.
authors.forename: Olena
authors.initials: O
authors.lastname: Andrukhova
authors.forename: Svetlana
authors.initials: S
authors.lastname: Slavic
authors.forename: Ute
authors.initials: U
authors.lastname: Zeitz
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Riesen
authors.forename: Monika S
authors.initials: MS
authors.lastname: Heppelmann
authors.forename: Tamas D
authors.initials: TD
authors.lastname: Ambrisko
authors.forename: Mato
authors.initials: M
authors.lastname: Markovic
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
authors.forename: Reinhold G
authors.initials: RG
authors.lastname: Erben
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D004549:Elastin / Q000378:metabolism; D004790:Enzyme Induction; D015870:Gene Expression; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques; D015533:Transcriptional Activation; D059289:Vascular Stiffness; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000502:physiology
chemical_list: D018167:Receptors, Calcitriol; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D009569:Nitric Oxide; D004549:Elastin; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse