title: Dietary Vitamin D and Its Metabolites Non-Genomically Stabilize the Endothelium.
abstract: Vitamin D is a known modulator of inflammation. Native dietary vitamin D3 is thought to be bio-inactive, and beneficial vitamin D3 effects are thought to be largely mediated by the metabolite 1,25(OH)2D3. Reduced serum levels of the most commonly measured precursor metabolite, 25(OH)D3, is linked to an increased risk of multiple inflammatory diseases, including: cardiovascular disease, arthritis, multiple sclerosis, and sepsis. Common to all of these diseases is the disruption of endothelial stability and an enhancement of vascular leak. We previously performed an unbiased chemical suppressor screen on a genetic model of vascular instability, and identified cholecalciferol (D3, dietary Vitamin D3) as a factor that had profound and immediate stabilizing and therapeutic effects in that model. In this manuscript we show that the presumed inactive sterol, D3, is actually a potent and general mediator of endothelial stability at physiologically relevant concentrations. We further demonstrate that this phenomenon is apparent in vitamin D3 metabolites 25(OH)D3 and 1,25(OH)2D3, and that the effects are independent of the canonical transcription-mediated vitamin D pathway. Our data suggests the presence of an alternative signaling modality by which D3 acts directly on endothelial cells to prevent vascular leak. The finding that D3 and its metabolites modulate endothelial stability may help explain the clinical correlations between low serum vitamin D levels and the many human diseases with well-described vascular dysfunction phenotypes.
authors.affiliation: Program in Molecular Medicine, University of Utah, Salt Lake City, Utah, 84112, United States of America; Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112, United States of America; Recursion Pharmaceuticals, LLC, Salt Lake City, Utah, 84108, United States of America.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Gibson
authors.affiliation: Program in Molecular Medicine, University of Utah, Salt Lake City, Utah, 84112, United States of America; Recursion Pharmaceuticals, LLC, Salt Lake City, Utah, 84108, United States of America; Department of Human Genetics, University of Utah, Salt Lake City, Utah, 84112, United States of America.
authors.forename: Chadwick T
authors.initials: CT
authors.lastname: Davis
authors.affiliation: Program in Molecular Medicine, University of Utah, Salt Lake City, Utah, 84112, United States of America.
authors.forename: Weiquan
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Program in Molecular Medicine, University of Utah, Salt Lake City, Utah, 84112, United States of America.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Bowman-Kirigin
authors.affiliation: Division of Geriatrics, Department of Medicine, University of Utah, Salt Lake City, Utah, 84112, United States of America.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Walker
authors.affiliation: The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, 610072, China.
authors.forename: Zhengfu
authors.initials: Z
authors.lastname: Tai
authors.affiliation: Program in Molecular Medicine, University of Utah, Salt Lake City, Utah, 84112, United States of America; Recursion Pharmaceuticals, LLC, Salt Lake City, Utah, 84108, United States of America.
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Thomas
authors.affiliation: Division of Geriatrics, Department of Medicine, University of Utah, Salt Lake City, Utah, 84112, United States of America.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Donato
authors.affiliation: Division of Geriatrics, Department of Medicine, University of Utah, Salt Lake City, Utah, 84112, United States of America.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Lesniewski
authors.affiliation: Program in Molecular Medicine, University of Utah, Salt Lake City, Utah, 84112, United States of America; Recursion Pharmaceuticals, LLC, Salt Lake City, Utah, 84108, United States of America; Department of Human Genetics, University of Utah, Salt Lake City, Utah, 84112, United States of America; The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, 610072, China; Division of Cardiology, Department of Medicine, University of Utah, Salt Lake City, Utah, 84112, United States of America; Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, 84112, United States of America; Cardiology Section, VA Salt Lake City Health Care System, Salt Lake City, Utah, 84112, United States of America.
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051379:Mice; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D014815:Vitamins; D002762:Cholecalciferol