Differential role of VEGF and ANGPTL4 in placental angiogenesis.

Abstract

The placenta is crucial for nutrient exchange at the maternal-fetal interface. Placental angiogenesis is regulated by angiogenic factors like vascular endothelial growth factor(VEGF) and angiopoietin-like protein 4 (ANGPTL4) that are produced by trophoblast giant cells. However, the differential roles of VEGF and ANGPTL4 in placental angiogenesis remain unclear. Using trophoblast stem cells and mouse placenta, we investigated the different roles of VEGF and ANGPTL4 by establishing a spatiotemporal expression profile. By in vitro differentiation of trophoblast stem cells, our results showed that trophoblast cells produced VEGF and ANGPTL4, albeit displaying a different expression pattern. VEGF was readily detected during early differentiation, whereas ANGPTL4 was only detected much later. In contrast to VEGF, ANGPTL4 resulted in a prolonged disruption of endothelial tight junction integrity, as evidenced by the transendothelial electrical resistance assay and a redistribution of zona occludens-1 protein. These observations suggested that angiogenesis may require the priming of endothelial cells and augmentation of the angiogenic effect by VEGF and ANGPTL4, respectively. The reduced expression of VEGF in late-stage pregnancy permitted ANGPTL4 to adopt a more prominent role in late placental angiogenesis. The dysregulation of angiogenic factors expression will impair angiogenesis, threatens placental development and leads to miscarriages.