The ability of ActRIIA-Fc to reverse established pulmonary inflammation and cardiopulmonary remodeling in severe experimental PAH indicates that the SMAD2/3-pathway ligands targeted by this agent mediate key interactions between cell types implicated in this disease, potentially including perivascular immune cells, endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts. This evidence concerns the gene SMAD2 and pulmonary arterial hypertension.