PPARγ/ETV2 axis regulates endothelial-to-mesenchymal transition in pulmonary hypertension

Endothelial-to-mesenchymal transition (EndoMT) plays an important role in pulmonary hypertension (PH) but the molecular mechanisms regulating EndoMT remain to be defined. We demonstrate that the axis of the transcription factors PPAR gamma (Peroxisome Proliferator-Activated Receptor gamma) and ETV2 (ETS variant 2) play important roles in the pathogenesis of PH. Decreased levels of the expression of PPAR gamma and ETV2 along with reduced endothelial and increased EndoMT markers are consistently observed in lungs and pulmonary artery endothelial cells (PAECs) of idiopathic pulmonary arterial hypertension patients, in hypoxia-exposed mouse lungs, human PAECs, and in induced-EndoMT cells. Etv2+/- mice spontaneously developed PH and right ventricular hypertrophy (RVH), associated with increased EndoMT markers and decreased EC markers. Interestingly, chronic hypoxia exacerbated right ventricular systolic pressure and RVH in Etv2+/- mice. PPAR gamma transcriptionally activates the ETV2 promoter. Consistently, while mice overexpressing endothelial PPAR gamma increases the expression of ETV2 and endothelial markers with reduced EndoMT markers, endothelial PPAR gamma KO mice show decreased ETV2 expression and enhanced EndoMT markers. Inducible overexpression of ETV2 under induced-EndoMT cell model reduces number of cells with mesenchymal morphology and decreases expression of mesenchymal markers with increased EC makers, compared to control. Therefore, our study suggests that PPAR gamma-ETV2 signaling regulates PH pathogenesis through EndoMT.