MiR-199a-3p deficiency induced by STAT3 activation drives smooth muscle cell phenotypic switching in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive vasculopathy characterized by pathological vascular remodeling, in which pulmonary artery smooth muscle cells (PASMCs) undergo phenotypic switching from a contractile to a synthetic state, driving excessive proliferation and migration. Here, we report that miR-199a-3p is significantly downregulated in both hypoxia/SU5416-induced PAH rat models and PDGF-BB-stimulated human PASMCs. Mechanistically, PDGF-BB stimulation induces the phosphorylation of STAT3, which directly binds to the TTCCCGGAA motif within the promoter of miR-199a-3p. This binding transcriptionally represses miR-199a-3p. Functional analyses demonstrated that miR-199a-3p overexpression maintains the PASMC contractile phenotype (upregulating MYH11 and SM22α) and suppresses proliferation and migration. Conversely, miR-199a-3p inhibition promotes synthetic phenotypic switching and activates the ERK/AKT signaling pathway. Furthermore, we identified YAP1 as a novel direct target of miR-199a-3p, linking miRNA downregulation to downstream proliferative signaling. Collectively, these findings establish a PDGF-BB/STAT3/miR-199a-3p/YAP1 regulatory axis that drives pathological PASMC phenotypic switching. This axis represents a promising therapeutic target for mitigating pulmonary vascular remodeling in PAH.