Vitamin D and the endothelium: basic, translational and clinical research updates Rinkoo Dalan a,b,c, ⁎, Huiling Liew a , Wai Kit Alvin Tan a , Daniel E.K. Chew a , Melvin Khee-Shing Leow a,b,c,d,e a Department of Endocrinology, Tan Tock Seng Hospital, Singapore b Duke-NUS Graduate Medical School, Singapore c Yong Loo Lin School of Medicine, NUS, Singapore d Brenner Centre for Molecular Medicine, Singapore e National University of Singapore, Singapore abstract article info Article history: Received 7 March 2014 Received in revised form 22 April 2014 Accepted 30 June 2014 Available online 8 July 2014 Keywords: Vitamin D Endothelium Cardiovascular Surrogate endpoints Survival outcomes Introduction and background: Vitamin D deficiency has been associated with cardiovascular diseases (CVDs) and its surrogate indicators such as endothelial dysfunction. It is an independent predictor of CVDs and all-cause mortality. Methods: We review the updated literature surrounding vitamin D and the endothelium spanning molecular, translational and clinical studies including randomized controlled trials (RCTs). We review the possible actions of vitamin D on the quiescent and activated endothelium including lessons from animal models. We review the recent literature for association of Vitamin D deficiency with endothelial dysfunction and cardiovascular complications, and for clinical trials done to look at the effect of vitamin D supplementation on the endothelium and cardiovascular outcome. Results and conclusion: Vitamin D deficiency is associated with endothelial dysfunction and cardiovascular diseases. Vitamin D stabilizes the quiescent endothelium, modulates certain stages of endothelial activation, and is involved in the repair of the damaged endothelium in vitro and in vivo. Twelve recent cross sectional studies, including 2086 subjects of varying ethnic groups, show an association between endothelial dysfunction and vitamin D deficiency. Yet 10 recent RCTs of vitamin D supplementation involving 824 subjects have failed to show significant improvements in endothelial function in the short term. So far, RCTs have not been able to confirm or refute the benefit of vitamin D supplementation on vascular mortality. Longer term randomized controlled trials using doses of vitamin D to optimize serum 25(OH)D concentrations to 20.0–40.0 ng/mL (50.0–100.0 nmol/L) or using vitamin D analogues with no calciotropic effects are needed to assess endothelial function and cardiovascular outcomes. © 2014 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). 1. Introduction Cardiovascular disease (CVD) remains the leading cause of mortality globally [1]. However, control of traditional risk factors does not result in a protection against CVD. Thus novel targets of treatment to reduce CVD remain of great interest. The endothelium is a complex endocrine and paracrine organ that plays a crucial role in the maintenance of vascular homeostasis. Impaired endothelial function has been postulated to provide a final common pathway by which multiple risk factors exert their deleterious effects on cardiovas- cular health and has been established as a powerful surrogate marker for cardiovascular risk [2]. IJC Metabolic & Endocrine 4 (2014) 4–17 Abbreviations: 1α,25(OH) 2 D 3 , 1 alpha,25-dihydroxyvitamin D 3 ; 25(OH)D, 25-hydroxyvitamin D; AGEs, Advanced glycation end-products; Akt, Protein kinase B; APC, Activated pro- tein C pathway; CFR, Coronary flow reserve; ChIP, Chromatin immunoprecipitation; CIMT, Carotid intima–media thickness; CVD, Cardiovascular disease; DBP, Vitamin D binding protein; EDHF, Endothelium-derived hyperpolarising factor; eNOS, Endothelial isoform of nitric oxide synthase; EPCs, Endothelial progenitor cells; ERK, Extracellular signal-regulated kinases; FMD, Flow mediated dilatation; H 2 O 2 , Hydrogen peroxide; HUVECs, Human umbilical vein endothelial cells; IHD, Ischemic heart disease; IkB-alpha, I-kappa-B-alpha; IL, Interleukins; IU, International Unit; LPS, Lipopolysaccharide; MCP-1, Monocyte Chemotactic Protein-1; MI, Myocardial Infarction; miRNA, micro-RNA; MM-LDL, Minimally modified-low density lipo- protein; MT1-MMP, Membrane type 1 matrix metalloproteinase; NFκB, Nuclear factor kappa-light-chain-enhancer of activated B cells; NO, Nitric oxide; p38, P38 mitogen-activated pro- tein kinases; PAI-1, Plasminogen activator inhibitor-1; Pro-vitamin D3, 7-dehydrocholesterol; RCT, Randomized controlled trial; RHI-PAT, Reactive hyperemia index–peripheral arterial tone; ROS, Reactive oxygen species; RXR, Retinoid X receptor; sICAM-1, serum Intercellular adhesion molecule-1; sVCAM-1, serum Vascular cell adhesion molecule-1; TM, Thrombomodulin; TNF-α, Tumour necrosis factor-alpha; uPAR, Urokinase receptor; UVA, Ultraviolet A; UVB, Ultraviolet B; VDR, Vitamin D receptor; VDRE, Vitamin D responsive element; Vitamin D2, Ergocalciferol; Vitamin D3, Cholecalciferol; VSMC, Vascular smooth muscle cell; vWF, von-Willebrand Factor. ⁎ Corresponding author at: Department of Endocrinology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore. E-mail address: rinkoo_dalan@ttsh.com.sg (R. Dalan). http://dx.doi.org/10.1016/j.ijcme.2014.06.003 2214-7624/© 2014 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). Contents lists available at ScienceDirect IJC Metabolic & Endocrine journal homepage: http://www.journals.elsevier.com/ijc-metabolic-and-endocrine