PI3 kinase p85/p55(Phospho Tyr467/199) Recombinant Rabbit Monoclonal Antibody [42F10]

Pulmonary vascular remodeling is a key structural alteration in pulmonary hypertension (PH), which involves intima, media, and adventitia remodeling. The media remodeling, composed predominantly of pulmonary artery smooth muscle cells (PASMCs), has been the focus of prior pathological descriptions and pathophysiological studies in PH. The cellular processes underlying muscularization caused by PASMCs proliferation are not completely understood. In the current study, we aim to explore the role of NR4A3 in PASMCs during the development of PH and the molecular mechanisms of act of regulating from the perspective of endothelial cell (EC)-smooth muscle cell (SMC) interaction. Utilizing a Sugen/hypoxia (SuHx) mouse model of PH, we found that NR4A3 expression was significantly upregulated in the medial layer of remodeled pulmonary arteries and in hypoxia-exposed human PASMCs in vitro . Specific knockdown of NR4A3 in PASMCs, achieved via adeno-associated virus vectors, markedly attenuated SuHx-induced elevation of right ventricular systolic pressure, pulmonary vascular remodeling and right ventricular hypertrophy. Functional assays confirmed that NR4A3 promotes PASMC proliferation confirmed by CCK-8, Ki-67 and EDU staining in vitro . Mechanistically, we identified a novel EC-to-SMC signaling axis. Under physiological conditions, endothelial caveolin-1 (Cav-1) directs the sorting of microRNA-17 (miR-17) into secreted extracellular vesicles (EVs). These EVs deliver miR-17 to adjacent PASMCs, where it post-transcriptionally represses NR4A3 expression. In PH, loss of endothelial Cav-1 disrupts this intercellular transfer, leading to NR4A3 depression. The upregulated NR4A3, in turn, involves in activation of the PI3K/AKT/mTOR signaling pathway, which drives PASMC proliferation and contributes to vascular remodeling. Our findings elucidate a Cav-1-dependent EV-mediated miR-17/NR4A3/PI3K-AKT-mTOR axis as a crucial mechanism in EC-SMC crosstalk during PH pathogenesis, providing a better understanding of the novel molecular mechanism underlying the EC-SMC crosstalk occurring in pulmonary vascular remodeling but also offer novel therapeutic targets for the prevention of pulmonary vascular remodeling in PH.