25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults

Abstract

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.

Figures

Figure 1

Brachial FMD (percent change (%Δ), top; absolute change (mmΔ); bottom) in 25(OH)D deficient, insufficient and sufficient groups (left); relation between serum 25(OH)D levels and FMD in the overall sample (%Δ, top; mmΔ, bottom) (right). Values are mean ± S.E. *P

Figure 2

Protein expression of NFκB p65 in vascular endothelial cells from 25(OH)D deficient, insufficient and sufficient subjects (left). FMD (%Δ) (center) and protein expression of NFκB p65 (right) in vascular endothelial cells following placebo vs. salsalate in lower and higher 25(OH)D groups .

Figure 3

Protein expression of IL-6 (left) and TNFα (right). Relation between 25(OH)D and IL-6 (middle). For all proteins, values are venous endothelial cell expression relative to human umbilical vein endothelial cell (HUVEC) control. *P

Figure 4

Protein expression of vitamin D receptor (VDR) (left) and 1-α hydroxylase (1-OHase) (middle) in vascular endothelial cells obtained from 25(OH)D deficient and sufficient subjects; representative images shown below. Relation between endothelial cell protein expression of 1-OHase and FMD (mmΔ) (right). For all proteins, values are venous endothelial cell expression relative to human umbilical vein endothelial cell (HUVEC) control. *P