β-Arrestin–Mediated Angiotensin II Type 1 Receptor Activation Promotes Pulmonary Vascular Remodeling in Pulmonary Hypertension

ABSTRACT: Visual Abstract Highlights • We tested the effects of a β-arrestin–biased agonist (TRV023) of the angiotensin II (AngII) type 1 receptor (AT1R), which acts as a vasodilator while not blocking cellular proliferation, compared to a balanced agonist, AngII, and an antagonist, losartan, in PAH.• In acute infusion, AngII increased right ventricular pressures while TRV023 and losartan did not. However, in chronic infusion in monocrotaline PAH rats, both TRV023 and AngII had significantly worse survival than losartan.• Both TRV023 and AngII enhanced proliferation and migration of pulmonary artery smooth muscle cells from patients with PAH.• β-arrestin-mediated AT1R signaling promotes vascular remodeling and worsens PAH, and suggests that the benefit of current PAH therapies is primarily through pulmonary vascular reverse remodeling. Summary Pulmonary arterial hypertension (PAH) is a disease of abnormal pulmonary vascular remodeling whose medical therapies are thought to primarily act as vasodilators but also may have effects on pulmonary vascular remodeling. The angiotensin II type 1 receptor (AT1R) is a G protein–coupled receptor that promotes vasoconstriction through heterotrimeric G proteins but also signals via β-arrestins, which promote cardioprotective effects and vasodilation through promoting cell survival. We found that an AT1R β-arrestin-biased agonist promoted vascular remodeling and worsened PAH, suggesting that the primary benefit of current PAH therapies is through pulmonary vascular reverse remodeling in addition to their vasodilation.

SUBMITTER: Ma Z 

PROVIDER: S-EPMC8617598 | biostudies-literature |

REPOSITORIES: biostudies-literature