Vitamin D improves the angiogenic properties of endothelial progenitor cells

Grundmann M, Haidar M, Placzko S, Niendorf R, Darashchonak N, Hubel CA, von Versen-Hoynck F. Vitamin D improves the angiogenic properties of endothelial progenitor cells. Am J Physiol Cell Physiol 303: C954-C962, 2012. First published August 29, 2012; doi: 10.1152/ajpcell.00030.2012.-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 immunocytochemistry and flow cytometry. Proliferation, total length of tubule formation on Matrigel, expression of VEGF mRNA, and pro-matrix metalloproteinases (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 D-3 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 D-3. Consequently, vitamin D-3 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.