**10. Endothelial dysfunction**

Vitamin D deficiency has been associated with endothelial dysfunction as measured by flow‐ mediated dilation (FMD) and reactive hyperemia peripheral arterial tonometry (RH‐PAT) [68].

A small study involving 23 asymptomatic subjects demonstrated that subjects with significant vitamin D deficiency had impaired brachial artery FMD, which improved after vitamin D replacement therapy. Recently, a stepwise change in FMD according to vitamin D status was demonstrated and an inverse association between serum 25(OH)D levels and vascular inflammatory markers was observed [33].

A prospective placebo‐controlled pilot study evaluated the effects of vitamin D repletion on endothelial function and inflammation in subjects with both vitamin D deficiency and CAD. The study was conducted over a 12‐week period in 90 subjects. RH‐PAT was used to estimate endothelial function. No significant differences between groups were found in reactive hyperemia index, blood pressure, and levels of hs‐CRP, IL‐6, IL‐12, interferon‐gamma (INF‐ gamma), and CXCL‐10 [68].

Similar results were obtained on a larger scale, the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS), that studied 852 men and found no significant relationship between vitamin D levels and endothelium‐dependent vasodilation, flow‐mediated vasodilation, and reflectance index. However, serum 25(OH)D level showed a negative correlation with SYNTAX score (angiographic grading tool to determine severity of coronary disease) and high‐sensi‐ tivity C‐reactive protein (hsCRP) level. Logistic regression analysis identified 25(OH)D as an independent factor related to high SYNTAX scores. Patients whose vitamin D levels were in the lowest 25(OH)D category (<20 ng/ml) were more often in the high SYNTAX scores group, with their incidence about twofold higher than those in the highest 25(OH)D category (>30 ng/ ml) [69].

In cross‐sectional analyses, low 25(OH)D (<20 ng/ml) was not associated with stiffer arteries after adjustment for cardiovascular disease risk factors (*P* > 0.4). PTH >65 pg/ml was associated with stiffer arteries after adjustment for cardiovascular disease risk factors, other than systolic blood pressure [70].

Black normotensive teenagers who received 2000 IU/d of vitamin D3 were compared with those who received 400 IU/d for 16 weeks in an RCT. Teenagers who received 400 IU/d of vitamin D3 increased their levels of 25(OH)D from 13.6 ± 4.2 to 23.9 ± 7.2 ng/ml and showed no reduction in arterial stiffness. In contrast, teenagers who received 2000 IU/d of vitamin D3 increased their meanlevelsof25(OH)Dfrom13.2±3.4to34.2±12.1ng/mlandsignificantlyloweredtheirarterial wall stiffness. This is supported by the observation that serum 25(OH)D levels <30 ng/ml were strongly associated with hypertension, elevated blood glucose, and metabolic syndrome in adolescents [63].
