Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis.
Cirrhosis consists of hepatocyte nodules surrounded by a highly vascularized fibrous tissue. We previously showed that the development of biliary cirrhosis in the rat is associated with the occurrence of hepatocellular hypoxia and the induction of hepatic angiogenesis. We herein examined the occurrence of hypoxia in an experimental model of diethylnitrosamine (DEN)-induced cirrhosis. We also determined whether hypoxia directly affects the expression of vascular endothelial growth factor (VEGF), of VEGF receptors (Flt-1, Flk-1), and of type I and type IV collagens in activated hepatic stellate cells (HSCs) and the expression of VEGF in hepatocytes. Our results show that in DEN-treated rats, although the progression of liver fibrosis is associated with hepatocellular hypoxia and angiogenesis, VEGF and Flt-1 expressions in the liver are increased and correlated with the density of microvessels. In vitro, hypoxia induces the expression of VEGF, Flt-1, and type I collagen in activated HSCs and that of VEGF in hepatocytes. In addition, we show that hypoxia-induced type I collagen expression in HSCs may occur independently of transforming growth factor beta1 (TGF-beta1) overexpression. In conclusion, the present study provides further evidence that hepatocellular hypoxia and angiogenesis progress together with fibrogenesis after liver injury and that hypoxia directly contributes to the progression of liver fibrosis.
Corpechot
Christophe
C
Service d'Hépatologie, the INSERM Unit 402, the Laboratoire Commun de Biologie Moléculaire, the Service d'Anatomie et de Cytologie Pathologiques, Centre Hospitalier Universitaire Saint-Antoine, Paris, France.
Barbu
Veronique
V
Wendum
Dominique
D
Kinnman
Nils
N
Rey
Colette
C
Poupon
Raoul
R
Housset
Chantal
C
Rosmorduc
Olivier
O
D000477:Alkylating Agents; D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics*; D024141:Collagen Type IV / Q000235:genetics; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005355:Fibrosis; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D000860:Hypoxia / Q000503:physiopathology*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D008222:Lymphokines / Q000235:genetics*; D008297:Male; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D000477:Alkylating Agents; D024042:Collagen Type I; D024141:Collagen Type IV; D016228:Endothelial Growth Factors; D016326:Extracellular Matrix Proteins; D008222:Lymphokines; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004052:Diethylnitrosamine; C501164:Flt1 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1