Zhang Shan, Sheng Min, Yu Dan, Qian Kechen, Zhang Yichen, Huang Wenhan, Ren Feifeng, Tang Lin
Department of Rheumatology and Immunology, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
J Inflamm Res. 2025 Sep 10;18:12401-12419. doi: 10.2147/JIR.S534282. eCollection 2025.
Angiotensin-(1-7) [Ang-(1-7)], a bioactive peptide of the renin‒angiotensin system, exerts potent anti-inflammatory, antifibrotic and metabolic regulatory effects. Ang-(1-7) inhibits synovial inflammation and bone destruction in collagen-induced arthritis (CIA) model mice, but its role in rheumatoid arthritis (RA) angiogenesis remains unknown. This study aimed to investigate the effect of Ang-(1-7) on synovial angiogenesis in CIA mice.
Arthritis scores and histopathology were used to assess the anti-inflammatory and joint damage-alleviating effects of Ang-(1-7) in CIA mice. Immunohistochemistry and immunofluorescence were used to detect vascular density in the synovium of CIA mice. The proliferation, migration, and tube formation abilities and the expression of angiogenic mediators of tumor necrosis factor-alpha (TNF-α)-induced human umbilical vein endothelial cells (HUVECs) were examined to assess Ang-(1-7) antiangiogenic activity. Immunofluorescence and Western blotting were used to analyze the protein levels, phosphorylation, and nuclear translocation of large tumor suppressor kinase 1 (LATS1) and Yes-associated protein (YAP) in CIA mice and TNF-α-induced HUVECs.
Ang-(1-7) treatment significantly reduced systemic inflammation in CIA mice, inhibited angiogenesis in the synovium, and attenuated synovial hyperplasia, inflammatory cell infiltration, and cartilage destruction. Ang-(1-7) also inhibited TNF-α-induced HUVEC proliferation, migration, and tube formation. Mechanistic investigations revealed that Ang-(1-7) exerted its therapeutic effects through modulation of the Hippo-YAP pathway. Ang-(1-7) significantly downregulated LATS1 and YAP expression while restoring their phosphorylation status. Furthermore, Ang-(1-7) inhibited YAP nuclear translocation, subsequently suppressing downstream targets, including hypoxia-inducible factor-1 (HIF-1), vascular endothelial growth factor (VEGF), and VEGF receptor 2 (VEGFR2). The effects of Ang-(1-7) were partially blocked by the Mas receptor antagonist A779.
Ang-(1-7) acts on the Mas receptor to regulate Hippo-YAP signaling, inhibit YAP activation, and suppress the production of HIF-1, VEGF and VEGFR2. This leads to the suppression of TNF-α-stimulated HUVEC activity, thereby attenuating synovial angiogenesis, inflammation, and joint damage in CIA mice.
血管紧张素 -（1 - 7）[Ang -（1 - 7）]是肾素 - 血管紧张素系统的一种生物活性肽，具有强大的抗炎、抗纤维化和代谢调节作用。Ang -（1 - 7）可抑制胶原诱导性关节炎（CIA）模型小鼠的滑膜炎症和骨破坏，但其在类风湿关节炎（RA）血管生成中的作用尚不清楚。本研究旨在探讨Ang -（1 - 7）对CIA小鼠滑膜血管生成的影响。
采用关节炎评分和组织病理学评估Ang -（1 - 7）对CIA小鼠的抗炎和减轻关节损伤的作用。采用免疫组织化学和免疫荧光检测CIA小鼠滑膜中的血管密度。检测肿瘤坏死因子 -α（TNF -α）诱导的人脐静脉内皮细胞（HUVECs）的增殖、迁移、管腔形成能力以及血管生成介质的表达，以评估Ang -（1 - 7）的抗血管生成活性。采用免疫荧光和蛋白质印迹分析CIA小鼠和TNF -α诱导的HUVECs中大型肿瘤抑制激酶1（LATS1）和Yes相关蛋白（YAP）的蛋白水平、磷酸化和核转位。
Ang -（1 - 7）治疗显著减轻了CIA小鼠的全身炎症，抑制了滑膜血管生成，并减轻了滑膜增生、炎性细胞浸润和软骨破坏。Ang -（1 - 7）还抑制了TNF -α诱导的HUVECs增殖、迁移和管腔形成。机制研究表明，Ang -（1 - 7）通过调节Hippo - YAP信号通路发挥其治疗作用。Ang -（1 - 7）显著下调LATS1和YAP表达，同时恢复其磷酸化状态。此外，Ang -（1 - 7）抑制YAP核转位，随后抑制下游靶点，包括缺氧诱导因子 -1（HIF - 1）、血管内皮生长因子（VEGF）和VEGF受体2（VEGFR2）。Ang -（1 - 7）的作用被Mas受体拮抗剂A779部分阻断。
Ang -（1 - 7）作用于Mas受体以调节Hippo - YAP信号，抑制YAP激活，并抑制HIF - 1、VEGF和VEGFR2的产生。这导致TNF -α刺激的HUVEC活性受到抑制，从而减轻CIA小鼠的滑膜血管生成、炎症和关节损伤。
