Vitamin D improves the angiogenic properties of endothelial progenitor cells

摘要

The main pathogenic feature of preeclampsia is maternal endothelial dysfunction that results from impaired angiogenesis and reduced endothelial repair capacity. In addition, preeclampsia risk is associated with vitamin D deficiency. We hypothesized that vitamin D_3 stimulates proangiogenic properties of endothelial colony-forming cells (ECFCs). ECFCs were obtained and cultured from cord blood and characterized by immunocytochem-istry and flow cytometry. Proliferation, total length of tubule formation on Matrigel, expression of VEGF mRNA, and pro-matrix met-alloproteinases (MMP)-2 activity were assessed after treatment of ECFCs with vitamin D_3. Specificity of the observed effects was tested by blocking the vitamin D receptor (VDR) or the VEGF signaling pathway. ECFCs treated with 10 nM vitamin D3 showed a 1.27 times higher tubule formation compared with vehicle-treated controls (1.27 +-0.19) as well as a 1.36 times higher proliferation rate (1.36 +- 0.06). Vitamin D_3 induced pro-MMP-2 activity (1.29 +- 0.17) and VEGF mRNA levels (1.74 +- 0.73) in ECFCs. VDR blocking by pyridoxal-5-phosphate (0.73 +- 0.19) or small interfering RNA (0.75 +- 0.17) and VEGF inhibition by Su5416 (0.56 +- 0.16) or soluble fms-like tyrosine kinase-1 (0.7 +- 0.14) reduced tubule formation and pro-MMP-2 activity (pyridoxal-5-phosphate: 0.84 +- 0.09; Su5416: 0.79 +- 0.11; or sFlt: 0.88 +- 0.13). This effect was neutralized by vitamin D3. Consequently, vitamin D3 significantly promoted angiogenesis in ECFCs in vitro possibly due to an increase in VEGF expression and pro-MMP-2 activity. Since angiogenesis is a crucial feature in the pathophysiology of preeclampsia these findings could explain the positive influence of vitamin D_3 in reducing preeclampsia risk.