Abstract
BACKGROUND: Pulmonary arterial hypertension remains a life-threatening disease despite advances in vasodilator therapy. Vascular remodeling, partly driven by pulmonary artery endothelial cell dysfunction, is accompanied by vasoactive mediators imbalance such as ET-1 (endothelin-1). Although endothelin receptor antagonists alleviate vasoconstriction, they incompletely address the remodeling process. We previously reported how endothelial-derived activin A promotes vascular remodeling, leading to the clinical development of the activin signaling inhibitor sotatercept, which improves outcomes when added to endothelin receptor antagonists. As both activin A and ET-1 originate from endothelial cells and promote remodeling, we investigated whether activin A regulates ET-1 production and activity in pulmonary arterial hypertension. METHODS: In vitro, we used pulmonary artery endothelial cell models of activin A overabundance alone or cocultured with pulmonary artery smooth muscle cells. Cells were treated with either the activin A inhibitor FST (follistatin), the endothelin receptor antagonist bosentan, the FST/bosentan combination, or vehicle for analysis. In vivo, we exposed wild-type or endothelial-specific INHBA (inhibin β-A)-overexpressing mice (VEcadherin-INHBA-Transgenic/VEcad-INHBA-Tg) to chronic hypoxia pulmonary hypertension model, with the addition of FST, bosentan, FST and bosentan, or vehicle treatments after the first week of hypoxia exposure. RESULTS: Activin A upregulated ET-1 expression via canonical SMAD2/3 (small mother against decapentaplegic family member 2/3) signaling in pulmonary artery endothelial cells. This induction, as well as ET-1-driven downstream effects-including reduced eNOS (endothelial NO synthase), pulmonary artery smooth muscle cell phenotypic switching, oxidative stress, and endothelial-to-mesenchymal transition-was reversed by FST alone or in combination with bosentan. In vivo, FST-based therapy achieved greater hemodynamic, right ventricular remodeling, and vascular structural normalization in wild-type and VEcad-INHBA-Tg mice than bosentan alone, accompanied by stronger ET-1 suppression. CONCLUSIONS: We identified ET-1 as a downstream effector of activin A in pulmonary arterial hypertension development, supporting activin A blockade as a strategy to inhibit ET-1-mediated vasoconstriction and remodeling. This mechanistic link provides a rationale for the rapid clinical benefits observed with sotatercept and suggests its potential role earlier in the pulmonary arterial hypertension treatment paradigm.