Hypoxia-induced VEGF and collagen I expressions are... : Hepatology (original) (raw)

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Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis

Corpechot, Christophe1, 2; Barbu, Veronique2, 3; Wendum, Dominique4; Kinnman, Nils1, 2; Rey, Colette2; Poupon, Raoul1, 2; Housset, Chantal1, 2; Rosmorduc, Olivier*,1,2

1 Service d'Hépatologie, Centre Hospitalier Universitaire Saint-Antoine, Paris, France

2 INSERM Unit 402, Centre Hospitalier Universitaire Saint-Antoine, Paris, France

3 Laboratoire Commun de Biologie Moléculaire, Centre Hospitalier Universitaire Saint-Antoine, Paris, France

4 Service d'Anatomie et de Cytologie Pathologiques, Centre Hospitalier Universitaire Saint-Antoine, Paris, France

E-mail:[email protected]

*Address reprint requests to: Service d'Hépatologie, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France. fax: (33)1 49 28 21 07.

Received August 06, 2001; accepted January 23, 2002; previously published online December 30, 2003

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.