Angiotensin-(1-7) Inhibits Angiogenesis and Alleviates Joint Damage in CIA Mice via the Hippo-YAP Pathway.

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.