title: Peroxisome proliferator-activated receptor-γ interrupts angiogenic signal transduction by transrepression of platelet-derived growth factor-β receptor in hepatic stellate cells.
abstract: Hepatic stellate cells (HSCs) are liver-specific pericytes that are recruited to vessels and secret pro-angiogenic cytokines, and thus actively involved in pathological vascularization during liver fibrosis. Peroxisome proliferator-activated receptor-γ (PPARγ) is a switch molecule controlling HSC activation. We investigated PPARγ regulation of angiogenic signal transduction and the molecular mechanisms involved in HSCs. Primary rat HSCs and liver sinusoidal endothelial cells (LSECs) were isolated and used in this study. Boyden chamber and tubulogenesis assays, identified that focal adhesion kinase (FAK)-RhoA signaling activated by platelet-derived growth factor (PDGF) was required for HSC motility and the associated vascularization. PDGF also stimulated vascular endothelial growth factor (VEGF) expression and HSC-driven vascularization through 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 through transrepression of PDGF-β receptor leading to reduced HSC motility, reduced VEGF expression, and thereby attenuated HSC-driven angiogenesis. PPARγ could be a molecular target for preventing vascular remolding in hepatic fibrosis.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Desong
authors.initials: D
authors.lastname: Kong
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Naqi
authors.initials: N
authors.lastname: Lian
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zhu
authors.forename: Yin
authors.initials: Y
authors.lastname: Lu
authors.forename: Shizhong
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D051417:Focal Adhesion Kinase 1; D047495:PPAR gamma; D019869:Phosphatidylinositol 3-Kinases; D010982:Platelet-Derived Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D020797:Receptor, Platelet-Derived Growth Factor beta; D012097:Repressor Proteins; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; D020742:rhoA GTP-Binding Protein
keywords: Angiogenesis; Hepatic stellate cell; Peroxisome proliferator-activated receptor-γ; Platelet-derived growth factor-β receptor; Transrepression