G Protein-coupled Receptor 30 Regulates Trophoblast Invasion And Its Deficiency Is Associated With Preeclampsia Running title: Preeclampsia is associated with compromised G Protein- coupled Receptor 30 expressison, which is involved in regulating trophoblast invasion

Preeclampsia (PE) is known to be associated with reduced circulating levels of estrogen. The effects of estrogen in PE are normally mediated by the classical estrogen receptors (ERs). Intriguingly, a novel estrogen receptor, G-protein coupled receptor 30 (GPR30), has been recently found to play an important role in several estrogenic effects. However, the mechanisms by which GPR30 may mediate the development of PE remain unknown. We observed that the expression of GPR30 in placental trophoblast cells is lower in preeclamptic placentas compared with normotensive controls. We then investigated the role of GPR30 in trophoblast cell invasion by utilizing placental explants and the immortalized human trophoblast cell line (HTR8/SVneo). The selective GPR30 agonist G1 and a general estrogen receptors agonist 17-β-estradiol (E2), both improved trophoblast cells invasion by up-regulating MMP9 expression and the PI3K-Akt signaling pathway. This effect was abolished by a selective GPR30 inhibitor G15, implying that GPR30 may be involved in regulating trophoblast invasion,and that deregulation of this receptor may result in the development of PE. The present study suggests that GPR30 is a critical regulator of trophoblast cell invasion, and as such may be a potential therapeutic interventional target for PE and other pregnancy complications resulting from impaired trophoblast invasion.