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.

The anti-inflammatory and joint-protective effects of Ang-(1-7) were assessed in CIA mice using clinical arthritis scoring and histopathological analysis. Synovial vascular density was evaluated by immunohistochemistry and immunofluorescence. In vitro, human umbilical vein endothelial cells (HUVECs) were stimulated with tumor necrosis factor-alpha (TNF-α) to model inflammatory angiogenesis, and the effects of Ang-(1-7) on endothelial proliferation, migration, tube formation, and the expression of angiogenic mediators were examined. Protein expression, phosphorylation status, and nuclear translocation of large tumor suppressor kinase 1 (LATS1) and Yes-associated protein (YAP) were analyzed in synovial tissues of CIA mice and TNF-α-induced HUVECs using immunofluorescence and western blotting. The Mas receptor antagonist A779 was used to determine the involvement of the Mas receptor in mediating the effects of Ang-(1-7).

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.