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 (%Delta: 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 kappa B was greater in deficient versus sufficient subjects (0.59 +/- 0.07 versus 0.44 +/- 0.05; P<0.05), and inhibition of nuclear factor kappa B (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-alpha 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 kappa B-related inflammation. Reduced vitamin D receptor and 1-alpha hydroxylase may be molecular mechanisms linking vitamin D insufficiency to endothelial dysfunction. (Hypertension. 2011; 57:63-69.)