Vitamin D supplementation in healthy adults lowers plasma thrombospondin-1 levels : a novel vitamin D target?

Introduction: Vitamin D deficiency is increasingly prevalent in the general population and is associated with cardiometabolic dysfunction. Thrombospondin-1 (TSP-1) is a potent inhibitor of the nitric oxide/cyclic GMP (NO/cGMP) signaling pathway in vascular cells, and contributes to vascular endothelial dysfunction. Several in vitro studies have shown that vitamin D analogs markedly down-regulate TSP-1 mRNA and protein expressions in human aortic smooth muscle cells. Hypothesis: In this clinical intervention study, we hypothesized that in vitamin D insufficient healthy subjects: 1) low 25-hydroxyvitamin D3 (25-OHD3) is associated with elevated plasma concentrations of TSP-1, and 2) vitamin D supplementation significantly reduces TSP-1 concentrations. Methods and Results: Healthy adults (n=31) (age 45±10 years) (BMI 28.2±5.9 Kg/m2) (mean±SD) without any pre-existing CV disease or diabetes, with vitamin D insufficiency (25-hydroxyvitamin D3 levels (25(OH)D3) ≤ 30 ng/mL) were recruited. Vitamin D administration (2000 IU/day for 12 weeks) significantly increased 25(OH)D3 level from 19±1.2 ng/ml to 39±1.6 ng/ml (mean ± SEM), p≤0.001. Plasma TSP-1 concentrations, measured by solid-phase ELISA, inversely correlated with 25(OH)D3 levels at baseline (r 2 = -0.530, p = 0.015). TSP-1 concentrations were markedly reduced following vitamin D supplementation (baseline 454.2±74.6 ng/ml Vs after 12 weeks 241.4±51.3 ng/ml (mean±SEM), p≤0.001). With vitamin D supplementation, there were no changes in either inhibition of ADP-induced platelet aggregation by sodium nitroprusside, or plasma asymmetric dimethylarginine (ADMA). Vitamin D supplementation significantly lowered systolic blood pressure (p=0.007), and diastolic blood pressure (p=0.008) levels. Conclusions: Our findings provide conclusive clinical evidence that vitamin D deficiency is associated with increased TSP-1 levels, and the reversal of the vitamin D deficient state markedly reduces TSP-1 concentrations. These findings support the evolving concept that vitamin D deficiency may be linked to impaired vascular NO signaling, and that early targeted vitamin D supplementation in deficient but otherwise healthy adults could prevent development of cardiometabolic diseases.