Angiopoietin-2-mediated integrin α5β1 and FAK signaling contributes to pulmonary arterial hypertension pathogenesis.

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by pulmonary vascular remodeling and right heart failure, in which endothelial dysfunction plays a central role. Angiopoietin-2 (ANGPT2) has been implicated in endothelial injury and vascular remodeling in multiple diseases; however, its role in hypoxic PAH remains incompletely understood. This study investigated the role and underlying mechanisms of ANGPT2 in PAH, with a particular focus on endothelial integrity, permeability, and vascular remodeling. Gene expression profiling was performed using lung tissues from patients with PAH, and ANGPT2 expression was further evaluated in plasma and lung tissues. Its functional role was examined in hypoxia-induced and Sugen/hypoxia (SuHx)-induced animal models of PAH. The effects of ANGPT2 inhibition by AAV-shANGPT2 delivery on hemodynamics, right ventricular function, and vascular remodeling were assessed. In vitro, pulmonary artery endothelial cells (PAECs) were used to evaluate the effects of ANGPT2 on proliferation, migration, and extracellular matrix remodeling. ANGPT2 expression was significantly increased in patients with PAH and in experimental models, and its levels correlated with indices of disease severity. Inhibition of ANGPT2 attenuated pulmonary hypertension, reduced right ventricular hypertrophy, and ameliorated pulmonary vascular remodeling, including collagen deposition and small-vessel muscularization. In PAECs, ANGPT2 inhibition restored impaired migration and tube formation and attenuated hypoxia-induced cell cycle progression. Mechanistically, ANGPT2 regulated integrin expression and activated focal adhesion kinase (FAK) signaling, thereby influencing endothelial adhesion, migration, and extracellular matrix remodeling. Collectively, these findings identify ANGPT2 as an important mediator of pulmonary vascular remodeling in experimental PAH and support ANGPT2 inhibition as a potential therapeutic approach warranting further preclinical investigation.