Peroxisome proliferator-activated receptor-γ interrupts angiogenic signal transduction via transrepression of platelet-derived growth factor-β receptor in hepatic stellate cells

Hepatic stellate cells (HSCs) are liver-specific pericytes with capabilities to recruit to vessels and secret pro-angiogenic cytokines and thus actively involved in pathologic vascularization during liver fibrosis. Peroxisome proliferator-activated receptor-γ (PPARγ) is a switch molecule controlling HSC activation. Herein we investigated the PPARγ regulation of angiogenic signal transduction and the molecular mechanisms in HSCs. Primary rat HSCs and liver sinusoidal endothelial cells (LSECs) were isolated and used in this study. Using Boyden chamber assay and tubulogenesis assay, we found that focal adhesion kinase (FAK)/RhoA signaling activated by platelet-derived growth factor (PDGF) was required for HSC motility and associated vascularization. PDGF also simulated vascular endothelial growth factor (VEGF) expression and HSC-driven vascularization via signals mediated by extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR). Gain- and loss-of-function analyses demonstrated that activation of PPARγ interrupted FAK/RhoA, ERK and mTOR cascades and inhibited HSC-based vascularization. Molecular evidence further revealed that PPARγ attenuation of HSC angiogenic properties was dependent on inhibition of PDGF-β receptor expression. We concluded that PPARγ inhibited angiogenic signal transduction via transrepression of PDGF-β receptor leading to inhibited HSC motility, reduced VEGF expression, and thereby attenuated HSC-driven angiogenesis. PPARγ could be a molecular target for preventing vascular remolding in hepatic fibrosis.