25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults.
We tested the hypothesis that vascular endothelial function, assessed by endothelium-dependent dilation, is related to serum vitamin D status among middle-aged and older adults without clinical disease, and that this is linked to inflammation. Brachial artery flow-mediated dilation, a measure of endothelium-dependent dilation, was lower (P<0.01) in vitamin D-insufficient (3.7 ± 0.2%; serum 25-hydroxyvitamin D [25(OH)D]: 20 to 29 ng/mL; 62 ± 1 years of age; n = 31; mean± SE) and vitamin D-deficient (3.2 ± 0.3%; 25(OH)D: <20 ng/mL; 63 ± 2 years of age; n = 22) versus vitamin D-sufficient (4.6 ± 0.4%; 25(OH)D: >29 ng/mL; 61 ± 1 years of age; n = 22) subjects, whereas endothelium-independent dilation (brachial dilation to sublingual nitroglycerine) did not differ (P = 0.45). Among all subjects, brachial flow-mediated dilation was positively related to serum 25(OH)D (%Δ: r = 0.35; P<0.01) but not 1,25-dihydroxyvitamin D (r = -0.06; P = 0.61), the active form of vitamin D. Vascular endothelial cell expression of the proinflammatory transcription factor nuclear factor κB was greater in deficient versus sufficient subjects (0.59 ± 0.07 versus 0.44 ± 0.05; P<0.05), and inhibition of nuclear factor κB (4 days oral salsalate) improved flow-mediated dilation to a greater extent in subjects with lower versus higher 25(OH)D (+3.7 ± 0.6 versus +2.0 ± 0.2%; P<0.05). Endothelial cell expression of the downstream proinflammatory cytokine interleukin-6 also was higher in deficient versus sufficient subjects (0.67 ± 0.08 versus 0.47 ± 0.05; P<0.01) and inversely related to serum 25(OH)D level (r = -0.62; P<0.01), whereas vitamin D receptor and 1-α hydroxylase, the 25(OH)D to 1,25-dihydroxyvitamin D converting enzyme, were lower (P<0.05). Inadequate serum 25(OH)D is associated with vascular endothelial dysfunction among healthy middle-aged/older adults, and this is mediated in part by nuclear factor κB-related inflammation. Reduced vitamin D receptor and 1-α hydroxylase may be molecular mechanisms linking vitamin D insufficiency to endothelial dysfunction.
Department of Integrative Physiology, University of Colorado, Boulder, Colo 80309, USA.
Kristen L
KL
Jablonski
Michel
M
Chonchol
Gary L
GL
Pierce
Ashley E
AE
Walker
Douglas R
DR
Seals
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000032:analysis; D000368:Aged; D001916:Brachial Artery / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D015850:Interleukin-6 / Q000032:analysis; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000032:analysis / Q000037:antagonists & inhibitors; D005996:Nitroglycerin / Q000494:pharmacology; D018167:Receptors, Calcitriol / Q000032:analysis; D012459:Salicylates / Q000494:pharmacology; D014652:Vascular Diseases / Q000209:etiology* / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D014808:Vitamin D Deficiency / Q000150:complications* / Q000378:metabolism
D015850:Interleukin-6; D016328:NF-kappa B; D018167:Receptors, Calcitriol; D012459:Salicylates; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; C104450:25-hydroxyvitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D005996:Nitroglycerin; C014182:salicylsalicylic acid