PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension

Significance Lung endothelial cells express high levels of glucose metabolic enzymes, such as PFKFB3, and consequently produce large amounts of glucose metabolites. These metabolites are able to stabilize the cell signaling molecule HIF2A, similar to that which occurs under hypoxic conditions. This stabilization of HIF2A by glucose metabolites in lung endothelial cells stimulates production of growth and inflammatory factors, thereby enhancing proliferation and inflammation of the pulmonary vessels and exacerbating pulmonary hypertension (PH). In this study, blockade of endothelial PFKFB3 inhibits PH development in rodent models, suggesting that targeting glucose metabolic enzymes is a promising strategy for the treatment of PH.