Angiogenesis and liver fibrosis

Abstract

Recent data indicate that hepatic angiogenesis, regardless of the etiology, takes place in chronic liver diseases (CLDs) that are characterized by inflammation and progressive fibrosis. Because anti-angiogenic therapy has been found to be efficient in the prevention of fibrosis in experimental models of CLDs, it is suggested that blocking angiogenesis could be a promising therapeutic option in patients with advanced fibrosis. Consequently, efforts are being directed to revealing the mechanisms involved in angiogenesis during the progression of liver fibrosis. Literature evidences indicate that hepatic angiogenesis and fibrosis are closely related in both clinical and experimental conditions. Hypoxia is a major inducer of angiogenesis together with inflammation and hepatic stellate cells. These profibrogenic cells stand at the intersection between inflammation, angiogenesis and fibrosis and play also a pivotal role in angiogenesis. This review mainly focuses to give a clear view on the relevant features that communicate angiogenesis with progression of fibrosis in CLDs towards the-end point of cirrhosis that may be translated into future therapies. The pathogenesis of hepatic angiogenesis associated with portal hypertension, viral hepatitis, non-alcoholic fatty liver disease and alcoholic liver disease are also discussed to emphasize the various mechanisms involved in angiogenesis during liver fibrogenesis.

Keywords: Angiogenesis; Chronic liver disease; Cirrhosis; Fibrogenesis; Hepatic stellate cells; Hypoxia; Liver fibrosis; Vascular endothelial growth factor.

Figure 1

Link between angiogenesis, inflammation and fibrosis. Hypoxia plays a crucial role in the the activation of HIF-1. HIF-1α: Hypoxia inducible factor 1α; HIF-1β: Hypoxia inducible factor 1β; HRE: Hypoxia responsive elements; VHL: Von Hippel Lindau protein; PDH: Prolyl hydroxylated domain; VEGF: Vascular endothelial growth factor.

Figure 2

Phases of angiogenesis and the agents involved. NO: Nitric oxyde; VEGF:Vascular endothelial growth factor; MMPs: Matrix metalloproteinases; Ang-2: Angiopoietin 2; FGF: Fibroblast growth factor; BFGF: Basic fibroblast growth factor; HGF: Hepatocyte growth factor; TGF-α: Transforming growth factor-α; TGF-β: Transforming growth factor-β; TNF-α: Tumor necrosis factor-α; PDGF: Platelet derived growth factor; PAI: Plasminogen activator inhibitor; Ang-1: Angiopoietin-1; TIMP: Tissue inhibitor of metalloproteinase; TSP-1: Thrombospondin-1.

Figure 3

Structure and function of endothelium. In endothelial cells an increase in Tie-2 signaling via the Ang-1 receptor initiates phosphorylation of Akt, which in turn phosphorylates eNOS and survivin. Enzymatic activity of eNOS is also regulated by calcium, calmodulin, NADPH, and BH4. The conversion of L-arginine to NO by eNOS leads to the cyclic-GMP-mediated relaxation of smooth muscle cells. Ang: Angiopoietin; BH4: 5,6,7,8 tetrahydrobiopterine; eNOS: Endothelial nitric oxide synthase; FN: Fibronectin; NO: Nitric oxide; PECAM-1: Platelet/endothelial cell adhesion molecule 1; VN: Vitronectin; Ang-1: Angiopoietin-1; Ang-2: Angiopoietin-2; VEGF: Vascular endothelial growth factor.