Together with published studies, our observations are suggestive of blunted Smad2 and 3 signaling in human PAH PAVSMC and may be explained by desensitization of Smad2 and Smad3 due to prolonged exposure to self-secreted TGF-β1 and Activin A, or by pathological shift from canonical Smads to non-canonical signaling pathways. This evidence concerns the gene SMAD2 and pulmonary arterial hypertension.