We found that hypoxia-induced Edn1 expression is mediated by GCN2 activation via HIF-2α expression and that restored endothelial Edn1 expression in KO mice partially reversed the reduced PH phenotype, demonstrating the important role of the PDK1/GCN2/HIF-2α/EDN1 signaling axis in the pathogenesis of pulmonary vascular remodeling and PAH. The gene discussed is EPAS1; the disease is pulmonary arterial hypertension.