Prostaglandin F2α promotes angiogenesis and embryo-maternal interactions during implantation

Implantation in humans and other mammals is a critical period during which high embryonic mortality rates occur. Prostaglandins (PGs) are key mediators regulating interactions between the reproductive tract and the conceptus (embryo with extraembryonic membranes). Although the significance of PGF2 alpha as a regulator of corpus luteum regression is well established, the role of its high amounts in the uterine lumen in most mammals, regardless of placentation type, during the implantation period remains unresolved. We hypothesized that PGF2 alpha acting as an embryonic signal mediator contributes to pregnancy establishment. Using a porcine model, we demonstrated that the conceptus and its signal (estradiol-17 beta) elevated endometrial expression of PGF2 alpha receptor (PTGFR) in vivo and in vitro. PTGFR protein was expressed mainly in luminal epithelial (LE) and glandular epithelial cells and blood vessels in the endometrium. PGF2 alpha stimulated the MAPK1/3 pathway in endometrial LE cells that coincided with elevated gene expression and secretion of endometrial vascular endothelial growth factor A (VEGFA) protein. PGF2 alpha-PTGFR and adenylyl cyclase signaling were involved in this process. PGF2 alpha-induced VEGFA acting through its receptors stimulated proliferation of endometrial endothelial cells. Moreover, PGF2 alpha elevated gene expression of biglycan, matrix metalloproteinase 9, transforming growth factor beta 3, and interleukin 1 alpha in the endometrium. In summary, our study indicates that PGF2 alpha participates in pregnancy establishment by promoting angiogenesis and expression of genes involved in tissue remodeling and conceptus-maternal interactions in porcine endometrium during early pregnancy.