PROJECT SUMMARY Pulmonary hypertension (PH) is characterized by progressive increase of pulmonary vascular resistanceand obliterative pulmonary vascular remodeling that result in right heart hypertrophy failure and prematuredeath. The underlying mechanisms of vascular remodeling and obliterative vascular lesion formation remainunclear. Genetic mutations and variants were found in patients with idiopathic pulmonary arterial hypertension(PAH) and PAH with congenital heart disease. However the mechanistic role of endothelial SOX17 in regulatingpulmonary vascular remodeling in the pathogenesis of PH has not been reported. We hypothesis that endothelialSOX17 deficiency leading to activation of E2F1 signaling which contributes to endothelial hyperproliferation andanti-apoptosis in the pathogenesis of PH. We will 1) define the novel role of endothelial SOX17 in thepathogenesis of PH using multiple transgenic mouse and rat models. 2) delineate the molecular mechanismsdownstream of endothelial SOX17 deficiency in mediating pulmonary vascular remodeling and PH and 3) explorethe translational potential of targeting E2F1 signaling. Completing our proposed study will provide a noveltherapeutic strategy for the effective treatment of PH in patients.