Grupo de Reprodução e Farmacologia Celular, Laboratório de Bioquímica Farmacológica, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA-UFRGS), Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Ciências de Saúde: Ginecologia e Obstetrícia (PPGGO), Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
Programa de Pós-Graduação em Ciências de Saúde: Ginecologia e Obstetrícia (PPGGO), Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Grupo de Reprodução e Farmacologia Celular, Laboratório de Embriologia e Diferenciação Celular, Centro de Pesquisa Experimental (CPE), Hospital de Clínicas de Porto Alegre (HCPA-UFRGS), Porto Alegre, RS, Brazil.
Biochem Pharmacol. 2024 Jul;225:116280. doi: 10.1016/j.bcp.2024.116280. Epub 2024 May 11.
The pivotal role of human endometrial stromal cells (hESCs) in the development of endometriosis lies in their ability to adopt a pro-invasive and proinflammatory profile upon migration to areas outside the uterus. However, the molecular mechanisms involved in these events remain unclear. In this study, we investigated how angiotensin II (Ang II) affects the plasminogen-plasmin system in hESCs, and the mechanisms underlying cell proliferation, migration, matrix degradation, and inflammation. Precursors, receptors, and peptidases involved in angiotensin metabolism increased significantly in Ang II-treated hESCs. The expression and activity of tissue (tPA)- and urokinase (uPA)- type plasminogen activators and the receptor for uPA (uPAR) were induced in the presence of Ang II. The up-regulation of tPA-uPA/uPAR pathway significantly contributes to heightened plasmin production both on the surface of hESCs and in their conditioned media. As a result, the plasmin generation induced by Ang II enhances the degradation of fibrin and matrix proteins, while also boosting hESC viability, proliferation, and migration through the up-regulation of growth factor expression. Notably, Ang II-induced hESC migration was dependent on the generation of active plasmin on cell surface. Ang II regulates oxidative and inflammatory signalling in hESCs primarily via NADPH oxidase and through the up-regulation of proinflammatory cytokines and adhesion molecules. Interestingly, Ang II receptor (AT1R) blockage, decreased plasmin generation, tPA-uPA/uPAR expression and hESC migration. Our results suggest that Ang II/AT1R axis regulates hESC proliferation and migration through tPA-uPA/uPAR pathway activation and plasmin generation. We propose the Ang II/AT1R axis as a potential target for endometriosis treatment.
人子宫内膜基质细胞（hESCs）在子宫内膜异位症发展中的关键作用在于其在迁移到子宫外区域时能够表现出侵袭性和促炎特征。然而，这些事件涉及的分子机制尚不清楚。在这项研究中，我们研究了血管紧张素 II（Ang II）如何影响 hESCs 中的纤溶酶原-纤溶酶系统，以及细胞增殖、迁移、基质降解和炎症的潜在机制。Ang II 处理后的 hESCs 中，血管紧张素代谢的前体、受体和肽酶显著增加。在 Ang II 存在的情况下，组织型（tPA）和尿激酶（uPA）型纤溶酶原激活物及其受体（uPAR）的表达和活性被诱导。tPA-uPA/uPAR 通路的上调显著促进了 hESCs 表面和条件培养基中纤溶酶的产生。因此，Ang II 诱导的纤溶酶生成增强了纤维蛋白和基质蛋白的降解，同时通过上调生长因子的表达来提高 hESC 的活力、增殖和迁移。值得注意的是，Ang II 诱导的 hESC 迁移依赖于细胞表面活性纤溶酶的产生。Ang II 主要通过 NADPH 氧化酶和上调促炎细胞因子和粘附分子来调节 hESCs 中的氧化和炎症信号。有趣的是，Ang II 受体（AT1R）阻断、纤溶酶生成减少、tPA-uPA/uPAR 表达和 hESC 迁移减少。我们的结果表明，Ang II/AT1R 轴通过 tPA-uPA/uPAR 通路的激活和纤溶酶的产生来调节 hESC 的增殖和迁移。我们提出 Ang II/AT1R 轴可能成为子宫内膜异位症治疗的潜在靶点。
