Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
J Lipid Res. 2024 Oct;65(10):100636. doi: 10.1016/j.jlr.2024.100636. Epub 2024 Aug 31.
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 [H]PGD-binding activity was detected in the decidua of uteri, with PGD synthesis comparable to that of PGE 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 and PGE contribute to decidualization via a coordinated pathway of DP and EP4 receptors.
为了探究前列腺素（PGs）在子宫中的未知作用，我们分析了子宫中各种 PG 受体的表达。我们发现，三种 Gs 偶联 PG 受体 DP、EP2 和 EP4，在着床期到晚期妊娠的腔上皮细胞中表达。DP 表达也在中系膜区域的基质细胞中诱导，而 EP4 在着床期在反中系膜区域的基质细胞中表达。胚胎附着后 DP 诱导的时间与环氧化酶-2（COX-2）的诱导时间非常吻合；然而，COX-2 表达的基质细胞位于胚胎附近，而 DP 表达的基质细胞围绕着这些细胞位于中系膜侧。在子宫蜕膜中检测到特异性[H]PGD 结合活性，PGD 合成与着床期子宫中检测到的 PGE 相当。COX-2 特异性抑制剂塞来昔布的给药对蜕膜化产生不良影响，表现为着床部位的重量减轻，同时给予 DP 激动剂可恢复。DP 激动剂的这种挽救作用被 EP4 激动剂模拟，但不是 EP2 激动剂模拟。虽然 DP 信号的重要性在药理学上得到了证明，但 DP/EP2 双重缺陷并不影响着床和蜕膜化，表明 EP4 对这些过程有贡献。事实上，EP4 拮抗剂的给药对 DP/EP2 缺陷小鼠的蜕膜化有显著影响。这些结果表明，COX-2 衍生的 PGD 和 PGE 通过 DP 和 EP4 受体的协调途径促进蜕膜化。
