Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease.
Liver injury causes vascular disorganization and local tissue hypoxia starting early in disease course. In this context, hypoxia acts not only as an aggravating factor of cell damage and inflammation, but also as an inhibitor of liver regeneration, a major stimulus of angiogenesis and fibrogenesis, and a promoter of liver carcinogenesis. Many of the effects of hypoxia are mediated by hypoxia-inducible factor-1alpha (HIF-1alpha), an oxygen-sensitive transcription factor. Compared to cells in the periportal area, intralobular hepatic stellate cells (HSCs) are more responsive to hypoxia and like other pericytes play a key role in angiogenesis through interactions with endothelial cells VIA platelet-derived growth factor (PGDF) and vascular endothelial growth factor (VEGF) signaling, at the leading edge of fibrotic septa. Although required for successful liver repair, angiogenesis in cirrhosis may be inefficient because of the immaturity and permeability of VEGF-induced neo-vessels, and thereby may fail to correct liver hypoxia. The multiple receptor tyrosine kinase inhibitors, acting on VEGF and PDGF receptors, initially designed for cancer treatment, show in addition to therapeutic efficacy in patients with hepatocellular carcinoma, beneficial effects on many aspects of the progression of liver diseases, including, fibrosis, inflammation and portal hypertension.
Rosmorduc
Olivier
O
UPMC Univ Paris 06, Hôpital Saint-Antoine, Service d'Hépatologie, Paris, France. Chantal.Housset@inserm.fr
Housset
Chantal
C
D000818:Animals; D015687:Cell Hypoxia; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006975:Hypertension, Portal / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D008115:Liver Regeneration; D018919:Neovascularization, Physiologic; D010100:Oxygen / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; D010100:Oxygen