Prostaglandin E-2 receptor subtype EP2 gene expression in the mouse uterus coincides with differentiation of the luminal epithelium for implantation

Among the PGs, PGE(2) is considered especially important for implantation and decidualization. Four major PGE(2) receptor subtypes, EP1, EP2, EP3, and EP4, mediate various PGE(2) effects via their coupling to distinct signaling pathways. Previously, we have shown that the EP1, EP3, and EP4 genes are expressed in the periimplantation mouse uterus in a spatio-temporal manner, suggesting compartmentalized actions of PGE(2) during this period. In this study, we examined the expression of the EP2 gene in the mouse uterus during the periimplantation period (days 1-8) and during experimentally induced progesterone (P-4)-maintained delayed implantation and its resumption by 17 beta-estradiol (E-2). We also examined its regulation in the uterus by ovarian steroid hormones. Our results establish that EP2 messenger RNA (mRNA) is expressed exclusively in the luminal epithelium primarily on day 4 (the day of implantation) and day 5 (early implantation) of pregnancy. In (P-4)-maintained delayed implanting mice, EP2 mRNA was present in the luminal epithelium, and the expression was further enhanced regardless of the location of the blastocysts after reinitiation of implantation. This observation suggests little or no embryonic influence in regulating EP2 expression and, instead, shows its regulation by P-4 and E-2. Indeed, treatment with E-2 and/or P-4 exhibited unique regulation of this gene. The treatment of adult ovariectomized mice with E-2 down-regulated the basal levels of EP2 mRNA, whereas that with P-4 up-regulated its levels in the luminal epithelium. The up-regulation of EP2 mRNA levels by P-4 was further augmented by superimposition of the E-2 treatment, sug gesting a synergistic interaction between E-2 and P-4 in regulating this gene in the uterus. Collectively, the results suggest that EP2 could be a potential mediator of PGE(2) actions in regulating luminal epithelial differentiation and serve as a marker for uterine receptivity for implantation.