Department of Obstetrics and Gynecology, The First Hospital, Harbin Medical University, Harbin, China; Department of Obstetrics and Gynecology, LSUHSC-Shreveport, LA, USA.
Department of Obstetrics and Gynecology, LSUHSC-Shreveport, LA, USA.
J Steroid Biochem Mol Biol. 2014 Mar;140:56-62. doi: 10.1016/j.jsbmb.2013.11.017. Epub 2013 Dec 5.
Endothelial dysfunction associated with vitamin D deficiency has been linked to many chronic vascular diseases. Vitamin D elicits its bioactive actions by binding to its receptor, vitamin D receptor (VDR), on target cells and organs. In the present study, we investigated the role of VDR in response to 1,25(OH)₂D₃ stimulation and oxidative stress challenge in endothelial cells. We found that 1,25(OH)₂D₃ not only induced a dose- and time-dependent increase in VDR expression, but also induced up-regulation of vascular endothelial growth factor (VEGF) and its receptors (Flt-1 and KDR), as well as antioxidant CuZn-superoxide dismutase (CuZn-SOD) expression in endothelial cells. We demonstrated that inhibition of VDR by VDR siRNA blocked 1,25(OH)₂D₃ induced increased VEGF and KDR expression and prevented 1,25(OH)₂D₃ induced endothelial proliferation/migration. Using CoCl₂, a hypoxic mimicking agent, we found that hypoxia/oxidative stress not only reduced CuZn-SOD expression, but also down-regulated VDR expression in endothelial cells, which could be prevented by addition of 1,25(OH)₂D3 in culture. These findings are important indicating that VDR expression is inducible in endothelial cells and oxidative stress down-regulates VDR expression in endothelial cells. We conclude that sufficient vitamin D levels and proper VDR expression are fundamental for angiogenic and oxidative defense function in endothelial cells.
维生素 D 缺乏与内皮功能障碍有关，与许多慢性血管疾病有关。维生素 D 通过与靶细胞和器官上的维生素 D 受体 (VDR) 结合发挥其生物活性作用。在本研究中，我们研究了 VDR 在 1,25(OH)₂D₃刺激和内皮细胞氧化应激挑战中的作用。我们发现，1,25(OH)₂D₃不仅诱导 VDR 表达剂量和时间依赖性增加，还诱导血管内皮生长因子 (VEGF) 及其受体 (Flt-1 和 KDR) 的上调，以及抗氧化剂 CuZn-超氧化物歧化酶 (CuZn-SOD) 在内皮细胞中的表达。我们证明，通过 VDR siRNA 抑制 VDR 阻断了 1,25(OH)₂D₃诱导的 VEGF 和 KDR 表达增加，并防止了 1,25(OH)₂D₃诱导的内皮细胞增殖/迁移。使用 CoCl₂，一种缺氧模拟剂，我们发现缺氧/氧化应激不仅降低了 CuZn-SOD 表达，还下调了内皮细胞中的 VDR 表达，这可以通过在培养物中添加 1,25(OH)₂D3 来预防。这些发现很重要，表明 VDR 表达在内皮细胞中可诱导，氧化应激下调内皮细胞中的 VDR 表达。我们得出结论，足够的维生素 D 水平和适当的 VDR 表达是内皮细胞血管生成和氧化防御功能的基础。
