Uterine prostaglandin DP receptor-induced upon implantation contributes to decidualization together with EP4 receptor.

To investigate the yet-unknown roles of prostaglandins (PGs) in the uterus, we analyzed the expression of various PG receptors in the uterus. We found that three types of Gs-coupled PG receptors, DP, EP2, and EP4, were expressed in luminal epithelial cells from the peri-implantation period to late pregnancy. DP expression was also induced in stromal cells within the mesometrial region, whereas EP4 was expressed in stromal cells within the anti-mesometrial region during the peri-implantation period. The timing of DP induction after embryo attachment correlated well with that of cyclooxygenase-2 (COX-2); however, COX-2-expressing stromal cells were located in the vicinity of the embryo, whereas DP-expressing stromal cells surrounded these cells on the mesometrial side. Specific [ ³ H]PGD ₂ -binding activity was detected in the decidua of uteri, with PGD ₂ synthesis comparable to that of PGE ₂ detected in the uteri during the peri-implantation period. Administration of the COX-2-specific inhibitor celecoxib caused adverse effects on decidualization, as demonstrated by the attenuated weight of the implantation sites, which was recovered by the simultaneous administration of a DP agonist. Such a rescuing effect of the DP agonist was mimicked by an EP4 agonist, but not an EP2 agonist. While the importance of DP signaling was shown pharmacologically, DP/EP2 double deficiency did not affect implantation and decidualization, suggesting the contribution of EP4 to these processes. Indeed, administration of an EP4 antagonist substantially affected decidualization in DP/EP2-deficient mice. These results suggest that COX-2-derived PGD ₂ and PGE ₂ contribute to decidualization via a coordinated pathway of DP and EP4 receptors.
Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest regarding the contents of this article.
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