title: Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis.
abstract: BACKGROUND
  It has been shown that expression of the potent angiogenic factor, vascular endothelial growth factor (VEGF), and its receptors, flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2), increased during the development of liver fibrosis.
  
  
  OBJECTIVE
  To elucidate the in vivo role of interaction between VEGF and its receptors in liver fibrogenesis.
  
  
  METHODS
  A model of CCl(4) induced hepatic fibrosis was used to assess the role of VEGFR-1 and VEGFR-2 by means of specific neutralising monoclonal antibodies (R-1mAb and R-2mAb, respectively). R-1mAb and R-2mAb were administered after two weeks of treatment with CCl(4), and indices of fibrosis were assessed at eight weeks.
  
  
  RESULTS
  Hepatic VEGF mRNA expression significantly increased during the development of liver fibrosis. Both R-1mAb and R-2mAb treatments significantly attenuated the development of fibrosis associated with suppression of neovascularisation in the liver. Hepatic hydroxyproline and serum fibrosis markers were also suppressed. Furthermore, the number of alpha-smooth muscle actin positive cells and alpha1(I)-procollagen mRNA expression were significantly suppressed by R-1mAb and R-2mAb treatment. The inhibitory effect of R-2mAb was more potent than that of R-1mAb, and combination treatment with both mAbs almost completely attenuated fibrosis development. Our in vitro study showed that VEGF treatment significantly stimulated proliferation of both activated hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC). VEGF also significantly increased alpha1(I)-procollagen mRNA expression in activated HSC.
  
  
  CONCLUSIONS
  These results suggest that the interaction of VEGF and its receptor, which reflected the combined effects of both on HSC and SEC, was a prerequisite for liver fibrosis development.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Nara, Japan. yoshijih@naramed-u.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Yoshiji
authors.forename: S
authors.initials: S
authors.lastname: Kuriyama
authors.forename: J
authors.initials: J
authors.lastname: Yoshii
authors.forename: Y
authors.initials: Y
authors.lastname: Ikenaka
authors.forename: R
authors.initials: R
authors.lastname: Noguchi
authors.forename: D J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: K
authors.initials: K
authors.lastname: Yanase
authors.forename: T
authors.initials: T
authors.lastname: Namisaki
authors.forename: M
authors.initials: M
authors.lastname: Yamazaki
authors.forename: H
authors.initials: H
authors.lastname: Tsujinoue
authors.forename: H
authors.initials: H
authors.lastname: Imazu
authors.forename: T
authors.initials: T
authors.lastname: Masaki
authors.forename: H
authors.initials: H
authors.lastname: Fukui
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000209:etiology* / Q000473:pathology; D008222:Lymphokines / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2