title: Role of vascular endothelial growth factor in the pathophysiology of nonalcoholic steatohepatitis in two rodent models.
abstract: The pathophysiology of nonalcoholic steatohepatitis (NASH) should be approached as a multifactorial process. In several stages of NASH, a link between disease progression and hepatic microvasculature changes can be made. In this study we investigated the role of angiogenesis in two mouse models for NASH, and the effect of a preventive and therapeutic antiangiogenic treatment in a diet-induced mouse model for NASH. Protein and RNA levels of angiogenic and inflammatory factors were significantly up-regulated in the liver of C56BL/6 and db/db mice with NASH at different timepoints. To examine the effect of angiogenic factors on the disease progression of NASH, a prevention and treatment study was set up, blocking the placental growth factor (PlGF) or vascular endothelial growth factor receptor 2 (VEGFR2). Our study showed that treatment prevents the progression of NASH by attenuating steatosis and inflammation, both in a preventive and therapeutic setting, thereby confirming the hypothesis that angiogenic factors play an early role in the disease progression from steatosis to NASH. Anti-PlGF (αPlGF) did not significantly improve liver histology. Vascular corrosion casting showed a more disrupted liver vasculature in mice with NASH compared to controls. Treatment with αVEGFR2 showed an improvement of the liver vasculature. Moreover, fat-laden primary hepatocytes treated with αVEGFR2 stored significantly less lipids.
  
  
  CONCLUSIONS
  Our results demonstrate that there is an increased expression of angiogenic factors in the liver in different mouse models for NASH. We found that VEGFR2 blockage attenuates steatosis and inflammation in a diet-induced mouse model for NASH in a preventive and therapeutic setting. Our findings warrant further investigation of the role of angiogenesis in the pathophysiology in NASH.
authors.affiliation: Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium. stephanie.coulon@ugent.be
authors.forename: Stephanie
authors.initials: S
authors.lastname: Coulon
authors.forename: Vanessa
authors.initials: V
authors.lastname: Legry
authors.forename: Femke
authors.initials: F
authors.lastname: Heindryckx
authors.forename: Christophe
authors.initials: C
authors.lastname: Van Steenkiste
authors.forename: Christophe
authors.initials: C
authors.lastname: Casteleyn
authors.forename: Kim
authors.initials: K
authors.lastname: Olievier
authors.forename: Louis
authors.initials: L
authors.lastname: Libbrecht
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Bart
authors.initials: B
authors.lastname: Jonckx
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Stassen
authors.forename: Hans
authors.initials: H
authors.lastname: Van Vlierberghe
authors.forename: Isabelle
authors.initials: I
authors.lastname: Leclercq
authors.forename: Isabelle
authors.initials: I
authors.lastname: Colle
authors.forename: Anja
authors.initials: A
authors.lastname: Geerts
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002796:Choline Deficiency / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005234:Fatty Liver / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D066298:In Vitro Techniques; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D065626:Non-alcoholic Fatty Liver Disease; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000502:physiology
chemical_list: D020533:Angiogenesis Inhibitors; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D008715:Methionine; D040301:Vascular Endothelial Growth Factor Receptor-2