Estradiol-17β, a key embryonic signal, regulates gene expression and cellular functions in the porcine trophoblast

Early pregnancy is a highly coordinated process requiring precise embryo-maternal communication. Estradiol-17β (E2) is considered the primary conceptus-derived signal responsible for the maternal recognition of pregnancy in pigs. Successful pregnancy establishment requires two distinct peaks of E2 secretion by porcine conceptuses: during days 11-12 (the maternal recognition of pregnancy) and days 15-30 (implantation). Although the role of E2 in signaling to the maternal system is well established, its potential autocrine effects on conceptus development remain unclear. This study examined whether E2 regulates trophoblast function during the maternal recognition of pregnancy and implantation. We demonstrated that expression of estrogen receptors (ESR1, ESR2, GPER1) and selected pregnancy-related genes (FOXO3, GDF15, SERPINE1, ESRRB, ESRRG) changes during early pregnancy in the pig. E2 regulated the gene expression of its receptors (ESR1, ESR2, GPER1), genes involved in E2 synthesis (HSD17B1), prostaglandin synthesis (PTGS2, AKR1C4, PTGES), and key mediators of pregnancy establishment (IL1B2, SERPINE1, FOXO3, GDF15, ESRRB and ESRRG). Furthermore, E2, acting via nuclear estrogen receptors, enhanced trophoblast cell proliferation on days 12 and 15 of pregnancy, and increased adhesion as well as MAPK1/3 and PTK2 protein phosphorylation on day 15 of pregnancy. E2 stimulated cell proliferation via MAPK and PI3K/AKT/mTOR pathways, whereas E2-promoted adhesion was mediated via MAPK and PI3K/AKT signaling. Concluding, these findings indicate that E2 functions not only as a critical embryonic signal for the maternal recognition of pregnancy but also plays an autocrine role in conceptus development, regulating gene expression and trophoblast cell function during early gestation in pigs.