Hypoxia-induced Downregulation of SRC-3 Suppresses Trophoblastic Invasion and Migration Through Inhibition of the AKT/mTOR Pathway: Implications for the Pathogenesis of Preeclampsia

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 CoCl(2)-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 CoCl(2)-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.