RT Journal Article
SR Electronic
T1 Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 1347
OP 1354
DO 10.1136/gut.52.9.1347
VO 52
IS 9
A1 H Yoshiji
A1 S Kuriyama
A1 J Yoshii
A1 Y Ikenaka
A1 R Noguchi
A1 D J Hicklin
A1 Y Wu
A1 K Yanase
A1 T Namisaki
A1 M Yamazaki
A1 H Tsujinoue
A1 H Imazu
A1 T Masaki
A1 H Fukui
YR 2003
UL http://gut.bmj.com/content/52/9/1347.abstract
AB 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.