Hypoxia, angiogenesis and liver fibrogenesis in the progression of chronic liver diseases

Abstract

Angiogenesis is a dynamic, hypoxia-stimulated and growth factor-dependent process, and is currently referred to as the formation of new vessels from pre-existing blood vessels. Experimental and clinical studies have unequivocally reported that hepatic angiogenesis, irrespective of aetiology, occurs in conditions of chronic liver diseases (CLDs) characterized by perpetuation of cell injury and death, inflammatory response and progressive fibrogenesis. Angiogenesis and related changes in liver vascular architecture, that in turn concur to increase vascular resistance and portal hypertension and to decrease parenchymal perfusion, have been proposed to favour fibrogenic progression of the disease towards the end-point of cirrhosis. Moreover, hepatic angiogenesis has also been proposed to modulate the genesis of portal-systemic shunts and increase splanchnic blood flow, thus potentially affecting complications of cirrhosis. Hepatic angiogenesis is also crucial for the growth and progression of hepatocellular carcinoma. Recent literature has identified a number of cellular and molecular mechanisms governing the cross-talk between angiogenesis and fibrogenesis, with a specific emphasis on the crucial role of hypoxic conditions and hepatic stellate cells, particularly when activated to the myofibroblast-like pro-fibrogenic phenotype. Experimental anti-angiogenic therapy has been proven to be effective in limiting the progression of CLDs in animal models. From a clinical point of view, anti-angiogenic therapy is currently emerging as a new pharmacologic intervention in patients with advanced fibrosis and cirrhosis.

Figure 1

Immunohistochemical analysis performed on paraffin liver sections from patients with hepatitis C virus (HCV)-related liver cirrhosis (METAVIR F4). Sections (2 μm thick) were incubated with specific antibodies raised against HIF-2α or α-SMA that positively stain cells exposed to hypoxia (HIF-2α) or myofibroblast-like cells (α-SMA). Primary antibodies were labelled by using EnVision, HRP-labelled System (DAKO) antibodies and visualized by 3’-diaminobenzidine substrate. Negative controls (C neg) were obtained by replacing the respective primary antibodies by isotype and concentrations matched irrelevant antibody. Original magnification is indicated.