HIF-1α regulates angiogenesis via Notch1/STAT3/ETBR pathway in trophoblastic cells

Abstract

<b>Background</b>: Preeclampsia is a pregnancy-related complication and the major cause to maternal and fetal mortality. Despite extensive studies, the pathogenesis of this disease still remains unknown. Here we explored the roles of HIF-1α and Notch1/ETBR in preeclampsia.<b>Methods</b>: Immunohistochemistry, RT-qPCR and western blot were used to measure levels of Notch1 and ETBR in placentas of preeclampsia patients. Transwell invasion assay and <i>in vitro</i> Matrigel assay were used to test the functions of Notch1, HIF-1α and ETBR in invasion and angiogenesis of trophoblast cells. In addition, we used reduced uterine perfusion pressure (RUPP) rat model to study preeclampsia <i>in vivo</i>.<b>Results</b>: We found that Notch1 and ETBR were down-regulated in the placenta of patients with preeclampsia. Hypoxia promoted invasion and angiogenesis of trophoblast cells, and up-regulated expressions of HIF-1α, Notch1/ETBR. Overexpression of Notch1 facilitated invasion and angiogenesis of trophoblast cells while HIF-1α inhibitor suppressed. Furthermore, Notch1 or ETBR could promote angiogenesis of trophoblast cells in RUPP rats.<b>Conclusions</b>: Our study reveals that HIF-1α and Notch1/ETBR play important roles in preeclampsia. Hypoxia-induced HIF-1αregulated Notch1/ETBR signaling, thereby modulating invasion and angiogenesis of trophoblast cells. These results shed light on molecular mechanisms of preeclampsia and provide potential targets for preeclampsia therapy.