Project Summary Pulmonary arterial hypertension (PAH) is characterized by a progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling that result in right heart hypertrophy, failure, and premature death. The underlying mechanisms of loss of capillary endothelial cells (ECs) and obliterative vascular lesion formation remain unclear. Our preliminary data showed that arterial programing was evident in human PAH patients and rodents. We hypothesize that general capillary ECs program to arterial ECs through HIF-2α-Cdk19/Sox17/Notch4 signaling which contributes to the pathogenesis of PAH. Completing our proposed study will provide a novel therapeutic strategy for the effective treatment of PAH in patients.