PH-LHD is aggravated by pulmonary artery (PA) remodeling, the pathomechanism of which is poorly characterized. We identified SMC hyperplasia as a hallmark of PA remodeling in PH-LHD. In vitro evaluation of human primary PA SMCs revealed increased cell migration in both LHD patients? prior to PH development (LHD w/o PH) and those from PH-LHD patients, with the latter also being characterized by increased proliferation, as compared to control SMCs. By electron microscopy, we identified the widening of endothelial BM in LHD w/o PH PAs and deterioration in PH-LHD. Mass spectrometry and atomic force microscopy assessments of decellularized ECM produced by endothelial cells (ECs) revealed enrichment in fibrillar collagens and increased stiffness in LHD w/o PH and PH-LHD, as compared to healthy EC ECM. As such, we hypothesized that remodeled and stiffened endothelial BM may trigger SMC hyperplasia by increasing cell migration and proliferation. Indeed, culturing of control SMCs on decellularized LHD w/o PH or PH-LHD endothelial ECM increased their proliferation and migration rates, while culturing of PH-LHD SMCs on decellularized control endothelial ECM inhibited these functions. Further in vitro analyses identified the involvement of the mechanosensitive YAP-1 in BM-to-SMC communication. Inhibition of Yap-1 by Verteporfin in a preclinical rat model of PH-LHD following aortic banding, reduced migration, and proliferation rates in isolated primary PA SMCs, and prevented PH, presenting a promising approach in the treatment of PH-LHD.