Investigation of endothelin-1 receptor antagonist bosentan in a rat endometriosis model

The study aimed to investigate the roles of endothelin-1 and endothelin receptors in a rat endometriosis model and to demonstrate how bosentan (BOS), an endothelin receptor blocker, could potentially serve as a novel treatment for endometriosis. Overall, 36 rats were divided into groups as follows: Group 1: Sham, Group 2: endometriosis, Group 3: Sham + BOS100 mg/kg, Group 4: endometriosis + BOS 25 mg/kg, Group 5: endometriosis + BOS 50 mg/kg, and Group 6: endometriosis + BOS 100 mg/kg. In the first laparotomy, an experimental endometriosis model was created by implanting a 0.5 × 0.5 cm2 piece of autologous endometrial tissue in Groups 2, 4, 5, and 6. After waiting for 4 weeks, a second laparotomy was performed to measure the endometriotic lesions in Groups 2, 4, 5, and 6. Following the measurements, Groups 4, 5, and 6 received oral administration of BOS at doses of 25 mg/kg, 50 mg/kg, and 100 mg/kg, respectively, for 2 weeks. Three groups received 100 mg/kg of BOS during the same time period. After the drug administration, a third laparotomy was performed, and the endometriotic lesions in Groups 2, 4, 5, and 6 were re-measured. Histopathological, immunohistochemical, biochemical, and molecular analyses of endometriotic lesion samples obtained after the experiment revealed a significant increase in the levels of TNF-α, TGF-β, MMP-9, ET-1, eNOS, VEGF, ETR-A, ETR-B, and MAPkinase in the experimental endometriosis group (Group 2). Conversely, these levels were significantly reduced in the BOS treatment groups (Groups 4, 5, and 6) in a dose-dependent manner compared to Group 2. Similarly, surface area measurements of endometriotic lesions showed a dose-dependent reduction in the BOS-treated groups (Groups 4, 5, and 6). The roles of endothelin-1 and its receptors in the pathophysiology and treatment of the endometriosis model of rats were demonstrated histopathologically, immunohistochemically, biochemically, and molecularly using BOS. This study can shed light on clinical treatment protocols for women with endometriosis. Graphical Abstract Possible effect mechanism of bosentan during endometriosis Similar content being viewed by others Data availability The data that support the findings of this study are available from the corresponding author, ZH, upon reasonable request.

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We thank the anonymous reviewers for examining this manuscript. This study was supported by the Atatürk University Scientific Research Projects Coordination Unit with project number TDK-2023-12249, for which the authors express their sincere gratitude. Funding This study was supported by the Atatürk University Scientific Research Projects Coordination Unit (grant number TDK-2023–12249). Author information Authors and Affiliations Contributions SSK and ZH conceived and designed research. SSK and ZH performed animal experiments and analysed the results. SSK and ZH wrote the manuscript. EC contributed to conceptualisation, writing and statistical analyses of data. ET performed all histopathological examinations. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used. Corresponding author Ethics declarations Ethics approval and consent to participate Approval was obtained for animal studies with the letter dated 26–09-2022 and numbered E-42190979–000-2200292976 from Atatürk University Animal Experiments Local Ethics Committee. Consent for publication All participants provided written informed consent for publication. Competing interests The authors declare no competing interests. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer 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. About this article Cite this article Karcioglu, S.S., Halici, Z., Cadirci, E. et al. Investigation of endothelin-1 receptor antagonist bosentan in a rat endometriosis model. Naunyn-Schmiedeberg's Arch Pharmacol 399, 8821–8835 (2026). https://doi.org/10.1007/s00210-025-04935-w Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s00210-025-04935-w