Ang-(1-7) and ET-1 interplay through Mas and ETB receptor interaction defines a novel vasoprotective mechanism

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Montezano, Augusto C. and Kuriakose, Jithin and Hood, Katie Y. and Sin, Yuan Yan and Camargo, Livia L. and Namkung, Yoon and Castro, Carlos H. and Santos, Robson A. and Alves-Lopes, Rheure and Tejeda, Gonzalo and Passaglia, Patricia and Basheer, Sehrish and Gallen, Emily and Findlay, Jane E. and Awan, Fazli R. and Laporte, Stéphane A. and MacLean, Margaret R. and Baillie, George S. and Touyz, Rhian M. (2025) Ang-(1-7) and ET-1 interplay through Mas and ETB receptor interaction defines a novel vasoprotective mechanism. Hypertension, 82 (2). pp. 267-281. ISSN 1524-4563 (https://doi.org/10.1161/HYPERTENSIONAHA.124.22693)

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Abstract

BACKGROUND: Ang-(1-7) (angiotensin (1-7)) via MasR (Mas receptor) opposes vaso-injurious actions of Ang II (angiotensin II) as shown in models of pulmonary hypertension. The underlying mechanisms remain unclear. We hypothesized cross talk between Ang-(1-7) and the protective arm of the ET-1 (endothelin-1) system involving MasR and ETBR (endothelin receptor type B). METHODS: To address this, we studied multiple models: in vivo, in a mouse model of ET-1–associated vascular injury (hypoxia-induced pulmonary hypertension); ex vivo, in isolated mouse arteries; and in vitro, in human endothelial cells. RESULTS: Pulmonary hypertension mice exhibited pulmonary vascular remodeling, endothelial dysfunction, and ET-1–induced hypercontractility. Ang-(1-7) treatment (14 days) ameliorated these effects and increased the expression of vascular ETBR. In human endothelial cells, Ang-(1-7)–induced activation of eNOS (endothelial NO synthase)/NO was attenuated by A779 (MasR antagonist) and BQ788 (ETBR antagonist). A779 inhibited ET-1–induced signaling. Coimmunoprecipitation and peptide array experiments demonstrated the interaction between MasR and ETBR. Binding sites for ETBR were mapped to MasR (amino acids 290–314). Binding sites for MasR on ETBR were identified (amino acids 176–200). Peptides that disrupt MasR:ETBR prevented Ang-(1-7) and ET-1 signaling. Using high-throughput screening, we identified compounds that enhance MasR:ETBR interaction, which we termed enhancers. Enhancers increased Ang-(1-7)–induced eNOS activity, NO production, and Ang-(1-7)–mediated vasorelaxation, and reduced contractile responses. CONCLUSIONS: We identify cross talk between Ang-(1-7) and ET-1 through MasR:ETBR interaction as a novel network that is vasoprotective. Promoting coactivity between these systems amplifies Ang-(1-7) signaling, increases ET-1/ETBR-mediated vascular actions, and attenuates the injurious effects of ET-1. Enhancing Ang-(1-7)/MasR:ET-1/ETBR signaling may have therapeutic potential in conditions associated with vascular damage.

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