PPARγ/ETV2 Axis Regulates Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension

Abstract

Endothelial-to-mesenchymal transition (EndoMT) plays an important role in pulmonary hypertension (PH). Also, the molecular mechanisms regulating EndoMT in PH remain to be defined. In this study, we first showed that reduced expression of the transcription factors ETV2 (ETS variant 2) and PPARγ (Peroxisome Proliferator-Activated Receptor gamma) along with reduced endothelial markers and increased EndoMT markers were consistently observed in lungs and pulmonary artery endothelial cells (PAECs) of idiopathic pulmonary arterial hypertension (IPAH) patients, in hypoxia-exposed mouse lungs, human PAECs, and in induced EndoMT cells. Base on this observation, we aimed to investigate the function of ETV2 and PPARγ in EndoMT. We have explored the function of ETV2 and PPARγ and its mechanism in PH using in Etv2+/- mice or PPARγ KO mice. Etv2+/- mice spontaneously developed PH and right ventricular hypertrophy, associated with increased EndoMT markers and decreased EC markers. PPARγ transcriptionally activated the ETV2 promoter. Endothelial PPARγ expression in mice is positively correlated with ETV2 expression, but inversely with EndoMT markers.Overexpression of ETV2 in hypoxia-exposed rat pulmonary artery led to vascular relaxation. We conclude that PPARγ-ETV2 signaling can function as a novel pathway in PH pathogenesis by attenuating EndoMT.