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Introduction Pulmonary arterial hypertension (PAH) is an umbrella term describing a group of diseases characterised by increased pulmonary vessel pressures that lead to right ventricular failure and death if left untreated. Dysregulated cellular metabolic function has been reported in endothelial cells (ECs) from PAH patients. Normal ECs generate more than 80% of their ATP via glycolysis, which enables rapid ATP production compared to oxidative phosphorylation. Thus, ECs can quickly adapt to pro-angiogenic stimuli and shift rapidly from quiescence to cellular functions such as proliferation, migration and apoptosis. Pulmonary artery ECs (PAECs) isolated from PAH patients are even more glycolytic, which is accompanied by a reduction in oxidative phosphorylation. This phenomenon is known as the Warburg effect and was initially reported in cancer. We have investigated the roles of both the splicing factor polypyrimidine-tract-binding protein (PTBP1) and its target, pyruvate kinase M2 (PKM2), known instigators of glycolysis, paying particular attention to the regulation of proliferation, migration, and apoptosis in PAH patient-derived endothelial cells.Methods We used blood outgrowth endothelial cells (BOECs) derived from healthy volunteers and PAH patients with BMPR2 mutations. The effects of apigenin, a trihydroxyflavone suppressor of the Warburg effect, and a PKM2 activator, TEPP-46, were used to manipulate the PTPB1-PKM2 axis both in this cell model and then in the PAH Sugen-hypoxia rat model.Results and discussion Drug specific effects were observed in both control and BMPR2 mutant BOECs, as TEPP-46 stabilised the tetrameric form of PKM2 while reducing the dimer; whereas apigenin reduced the tetrameric PKM2 and inhibited expression of PTBP1. Both drugs decreased levels of PTPB1 and reduced endothelial cell proliferation and apoptosis. Only apigenin decreased lactate production in both control and mutant BOECs. In the Sugen-hypoxia rat model, administration of TEPP-46 but not apigenin significantly ameliorated the elevated right ventricular systolic pressure and loss of body weight associated with Sugen-hypoxia.Conclusions We have shown that TEPP-46 treatment suppresses EC glycolysis, by repressing PKM2-driven glycolytic gene expression, with the functional effect of ameliorating the Sugen-hypoxia phenotype. This suggests that correcting endothelial cell dysfunction may improve the overall PAH phenotype.