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Hypoxia‐induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis
Author(s) -
Corpechot Christophe,
Barbu Veronique,
Wendum Dominique,
Kinnman Nils,
Rey Colette,
Poupon Raoul,
Housset Chantal,
Rosmorduc Olivier
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.32524
Subject(s) - angiogenesis , hypoxia (environmental) , cirrhosis , hepatic stellate cell , vascular endothelial growth factor , fibrosis , hypoxia inducible factors , pathology , cancer research , endocrinology , medicine , biology , chemistry , vegf receptors , biochemistry , organic chemistry , oxygen , gene
Abstract 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 β1 (TGF‐β1) 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.