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Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis
  1. H Yoshiji,
  2. S Kuriyama,
  3. J Yoshii,
  4. Y Ikenaka,
  5. R Noguchi,
  6. D J Hicklin,
  7. Y Wu,
  8. K Yanase,
  9. T Namisaki,
  10. M Yamazaki,
  11. H Tsujinoue,
  12. H Imazu,
  13. T Masaki,
  14. H Fukui
  1. 1Third Department of Internal Medicine, Nara Medical University, Nara, Japan
  2. 2Third Department of Internal Medicine, Kagawa Medical University, Kagawa, Japan
  3. 3Department of Immunology, ImClone Systems Incorporated, New York, NY, USA
  1. Correspondence to:
    Dr H Yoshiji, Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara 634-8522, Japan;


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.

Aims: To elucidate the in vivo role of interaction between VEGF and its receptors in liver fibrogenesis.

Methods: A model of CCl4 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 CCl4, 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 α-smooth muscle actin positive cells and α1(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 α1(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.

  • vascular endothelial growth factor
  • liver fibrosis
  • angiogenesis
  • hepatic stellate cells
  • α-SMA, α smooth muscle actin
  • ALT, aminotransferase aspartate
  • A-M, Azan-Mallory
  • ECM, extracellular matrix
  • EC, endothelial cells
  • HSC, hepatic stellate cells
  • IgG, immunogloblin G
  • mAb, neutralising monoclonal antibody
  • PCR, polymerase chain reaction
  • P-III-P, procollagen III-N-peptide
  • R-1mAb, VEGFR-1 monoclonal antibody
  • R-2mAb, VEGFR-2 monoclonal antibody
  • SEC, hepatic sinusoidal endothelial cells
  • VEGF, vascular endothelial growth factor
  • VEGFR-1, fms-like tyrosine kinase (flt-1)
  • VEGFR-2, kinase-insert domain-containing receptor/fetal liver kinase-1 (KDR/Flk-1)
  • vWF, von Willebrand factor
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