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 vascular remodeling and obliterative vascular lesion formation remain unclear. Fatty acid metabolism dysfunction is linked to PAH. However, the mechanistic role of fatty acid metabolism in regulating pulmonary vascular remodeling in the pathogenesis of PAH has not been reported. We hypothesize that endothelial fatty acid-binding proteins 4 and 5 (FABP4-5) regulate endothelial glycolysis and arterial programming through HIF-2a/SOX17 signaling which contributes to severe vascular remodeling in the pathogenesis of PAH. We will 1) define the novel role of endothelial FABP4-5 in the pathogenesis of PAH using multiple transgenic animal models. 2) delineate the cellular and molecular mechanisms that FABP4-5 induces arterial programming and pathogenesis of PAH. Completing our proposed study will provide a novel therapeutic strategy for the effective treatment of PAH in patients.