Hypoxia-induced Downregulation of SRC-3 Suppresses Trophoblastic Invasion and Migration Through Inhibition of the AKT/mTOR Pathway: Implications for the Pathogenesis of Preeclampsia.
journal contributionposted on 24.07.2019, 14:01 by C He, N Shan, P Xu, H Ge, Y Yuan, Y Liu, P Zhang, L Wen, F Zhang, L Xiong, C Peng, H Qi, C Tong, PN Baker
Preeclampsia (PE) is characterized by poor placentation, consequent on aberrant extravillous trophoblast (EVT) cell function during placental development. The SRC family of proteins is important during pregnancy, especially SRC-3, which regulates placental morphogenesis and embryo survival. Although SRC-3 expression in mouse trophoblast giant cells has been documented, its role in the functional regulation of extravillous trophoblasts and the development of PE remains unknown. This study found that SRC-3 expression was significantly lower in placentas from PE pregnancies as compared to uncomplicated pregnancies. Additionally, both CoCl2-mimicked hypoxia and suppression of endogenous SRC-3 expression by lentivirus short hairpin RNA attenuated the migration and invasion abilities of HTR-8/SVneo cells. Moreover, we demonstrated that SRC-3 physically interacts with AKT to regulate the migration and invasion of HTR-8 cells, via the AKT/mTOR pathway. We also found that the inhibition of HTR-8 cell migration and invasion by CoCl2-mimicked hypoxia was through the SRC-3/AKT/mTOR axis. Our findings indicate that, in early gestation, accumulation of HIF-1α inhibits the expression of SRC-3, which impairs extravillous trophoblastic invasion and migration by directly interacting with AKT. This potentially leads to insufficient uterine spiral artery remodeling and placental hypoperfusion, and thus the development of PE.