{"paper_id":"b0888a1b-491f-4d72-b5f2-4c2bb2ec98f3","body_text":"Abstract\nIn women of childbearing age, extensive decidualization, shedding and remodeling of the endometrium during the menstrual cycle are fundamental for successful pregnancy. The role of prostaglandins (PGs) in menstruation has long been proposed in humans, and the rate-limiting enzyme cyclooxygenase was shown to play a key role in endometrial breakdown and shedding in a mouse menstrual-like model in our previous study. However, the specific types of PGs involved and their respective roles remain unclear. Therefore, our objective was to investigate the mechanism through which PGs regulate endometrial disintegration. In this study, the microscopy was observed by HE; the protein levels of prostaglandins E1 (PGE1), prostaglandins E2 (PGE2), prostaglandin F2α (PGF2α) and Prostaglandin I2 (PGI2) were detected by ELISA; the mRNA level of Pfgfr2, Vascular Endothelial Growth Factor(Vegf), Angiostatin and Hypoxia inducible factor-1α (Hif1α) were examined by real-time PCR; PTGFR Receptor (PTGFR), VEGF, Angiostatin and HIF-1α protein levels were investigated by western blotting; the locations of protein were observed by Immunohistochemistry; HIF-1α binding PTGFR promoter was detected by Chromatin Immunoprecipitation (ChIP) and real-time PCR. We found that the concentrations of PGE1, PGE2, and PGF2α all increased significantly during this process. Furthermore, Ptgfr mRNA increased soon after Progesterone (P4) withdrawal, and PTGFR protein levels increased significantly during abundant endometrial breakdown and shedding processes. PTGFR inhibitors AL8810 significantly suppressed endometrial breakdown and shedding, promoted Angiostatin expression, and reduced VEGF-A expressions and vascular permeability. And HIF-1α and PTGFR were mainly located in the luminal/gland epithelium, vascular endothelium, and pre-decidual zone. Interestingly, HIF-1α directly bound to Ptgfr promoter. Moreover, a HIF-1α inhibitor 2-methoxyestradiol (2ME) significantly reduced PTGFR expression and suppressed endometrial breakdown which was in accord with PTGFR inhibitor’s effect. Similar changes occurred in human stromal cells relevant to menstruation in vitro. Our study provides evidence that PGF2α/PTGFR plays a vital role in endometrial breakdown via vascular changes that are regulated by HIF-1α during menstruation.\nGraphical Abstract\nSimilar content being viewed by others\nData Availability\nThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\nReferences\nPickles VR. 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The abstract graph was drawn by Figdraw.\nFunding\nThis work was funded by the National Natural Science Foundation of China (No. 81571410) and the Non-profit Central Research Institute Fund of the National Research Institute for Family Planning (No. 2023GJZD01, 2023GJZ04).\nAuthor information\nAuthors and Affiliations\nContributions\nX.X. study supervisor and fund acquisition; F.Z. and W.L. conceived and designed the experiments; F.Z. and S.G. operated the experiments; F.Z., X.C. and C.L. statistical analysis and data visualization; Z.L., X.Z., S.W. and J.W. mouse model assistant; B.H. and T.Z. result interpretation; S.W.4 wrote the manuscript.\nCorresponding author\nEthics declarations\nConflict of interest\nThe authors have no conflict of interest to declare.\nAdditional information\nPublisher's Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nRights and permissions\nSpringer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.\nAbout this article\nCite this article\nZhou, F., Wang, S., Lu, W. et al. The Essential Role of PGF2α/PTGFR in Molding Endometrial Breakdown and Vascular Dynamics, Regulated by HIF-1α in a Mouse Menstrual-like Model. Reprod. Sci. 31, 2718–2730 (2024). https://doi.org/10.1007/s43032-024-01526-7\nReceived:\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s43032-024-01526-7","source_license":"CC0","license_restricted":false}