Beta-arrestin-mediated Angiotensin II type 1 Receptor Activation Promotes Pulmonary Vascular Remodeling in Pulmonary Hypertension

Abstract

ObjectivesThe goal of this study was to test whether a {beta}-arrestin-biased agonist of the angiotensin II (AngII) type 1 receptor (AT1R), which acts as a vasodilator while not blocking cellular proliferation, would have positive effects compared to a balanced agonist, angiotensin II (AngII), or an antagonist, losartan, in pulmonary arterial hypertension (PAH). BackgroundPAH is a disease of abnormal pulmonary vascular remodeling whose treatment has focused on targeting vasoactive substances, such as inhibiting endothelin signaling and promoting prostacyclin signaling. PAH medical therapies are thought to primarily act as vasodilators, although they may also have effects on pulmonary vascular remodeling. There are a number of reports that blocking AT1R signaling can be beneficial in preclinical models of PAH. The AT1R is a G protein-coupled receptor (GPCR) that promotes vasoconstriction through heterotrimeric G proteins but also signals via {beta}-arrestins, which promote cardioprotective effects and vasodilation. MethodsWe compared the effects of a {beta}-arrestin-biased AT1R agonist, TRV120023 (TRV023), to a balanced agonist (AngII) and an antagonist (losartan) in preclinical PAH models. ResultsIn acute infusion studies, AngII increased right ventricular (RV) pressures while TRV023 did not. However, with chronic infusion in monocrotaline (MCT) PAH rats, TRV023 failed to improve hemodynamics or survival compared to AngII, while losartan significantly improved survival. Both TRV023 and AngII enhanced proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) from PAH patients, which was associated with the promotion of proliferative MAP kinase signaling. Conclusions{beta}-arrestin-mediated AT1R signaling promotes vascular remodeling and worsens PAH, and suggests that the primary benefit of current PAH therapies is through pulmonary vascular reverse remodeling and not vasodilation.