The active form of vitamin D, calcitriol, induces a complex dual upregulation of endothelin and nitric oxide in cultured endothelial cells

Abstract

Despite the presence of vitamin D receptor (VDR) in endothelial cells, the effect of vitamin D on endothelial function is unknown. An unbalanced production of vasoactive endothelial factors such as nitric oxide (NO) or endothelin-1 (ET-1) results in endothelial dysfunction, which can alter the normal cardiovascular function. Present experiments were devoted to assess the effect of active vitamin D (calcitriol) on the synthesis of endothelial vasoactive factors. The results were that, in cells, calcitriol increased ET-1 and NO productions, which were measured by ELISA and fluorimetric assay, respectively. Calcitriol also increased endothelin-converting enzyme-1 (ECE-1) and endothelial-nitric oxide synthase (eNOS) activities, their mRNA (qPCR), their protein expressions (Western-blot), and their promoter activities (transfection assays). Calcitriol did not change prepro-ET-1 mRNA. The effect was specific to VDR activation because when VDR was silenced by siRNA, the observed effects disappeared. Mechanisms involved in each upregulation differed. ECE-1 upregulation depended on AP-1 activation, whereas eNOS upregulation depended directly on VDR activation. To evaluate the in vivo consequences of acute calcitriol treatment, normal Wistar rats were treated with a single ip injection of 400 ng/kg calcitriol and euthanized 24 h later. Results confirmed those observed in cells, that production and expression of both factors were increased by calcitriol. Besides, calcitriol-treated rats showed a slight rise in mean blood pressure, which decreased when pretreated with FR-901533, an ECE-1 antagonist. We conclude that calcitriol increases the synthesis of both ET-1 and NO in endothelial cells. However, the ET-1 upregulation seems to be biologically more relevant, as animals acutely treated with calcitriol show slight increases in blood pressure.

Vitamin D Versus Placebo in Improvement of Endothelial Dysfunction: A Meta‐Analysis of Randomized Clinical Trials

“…One of the possible explanations why vitamin D was not found to improve overall ED in our meta-analysis may lay in the fact that vitamin D stimulates production of both vasoconstrictive endothelin-1 (ET-1) and vasodilator NO. Thus, an administration of vitamin D in cultured endothelial cells induced a complex dual upregulation of ET-1 and NO; which was shown in Wistar rats after administration of vitamin D [38]. Additionally, a slight rise in mean blood pressure was observed in Wistar rats treated with vitamin D. Likewise, ET-1 increase was observed in human coronary artery smooth muscle cells after exposure to vitamin D [39].…”

1,25-Dihydroxyvitamin D3 preserves intestinal epithelial barrier function from TNF-α induced injury via suppression of NF-kB p65 mediated MLCK-P-MLC signaling pathway

“…1,25(OH)2D3, also termed as calcitrol, was reported to protect barrier function in both the endothelial and epithelial cells [9,31]. Based on the previous reports, we set out to investigate the possible protective effect of 1,25(OH)2D3 on TNF-a induced barrier dysfunction and the underlying mechanisms.…”

Endothelial dysfunction and vascular disease - a 30th anniversary update

“…The improvement of endothelial function is attributable to increased expression/activity of eNOS and a greater production of NO together with inhibition of the increase in oxidative stress caused by endogenous angiotensin II (Martínez‐Miguel et al . , Ni et al . , Schulz et al .…”