Angiogenesis in liver disease

Abstract

Angiogenesis and disruption of liver vascular architecture have been linked to progression to cirrhosis and liver cancer (HCC) in chronic liver diseases, which contributes both to increased hepatic vascular resistance and portal hypertension and to decreased hepatocyte perfusion. On the other hand, recent evidence shows that angiogenesis modulates the formation of portal-systemic collaterals and the increased splanchnic blood flow which are involved in the life threatening complications of cirrhosis. Finally, angiogenesis plays a key role in the growth of tumours, suggesting that interference with angiogenesis may prevent or delay the development of HCC. This review summarizes current knowledge on the molecular mechanisms of liver angiogenesis and on the consequences of angiogenesis in chronic liver disease. On the other hand, it presents the different strategies that have been used in experimental models to counteract excessive angiogenesis and its potential role in preventing transition to cirrhosis, development of portal hypertension and its consequences, and its application in the treatment of hepatocellular carcinoma.

Cellular and molecular mechanisms in liver fibrogenesis

“…Although angiogenesis may be considered as beneficial for tissue growth and regeneration as well as for growth and repair of injured tissues, the same process is currently believed to also fuel inflammatory and fibro-proliferative diseases as well as malignancies in different organs, including chronically injured liver. Pertinent to this review, literature data provided in the last decade have unequivocally linked angiogenesis to liver fibrogenesis and CLDs progression, suggesting that angiogenesis may favor fibrogenesis [81,82]. The presence of hypoxic areas within liver parenchyma in the scenario of a developing CLD is the most obvious (but not the only one) stimulus able to switch on the transcription of pro-angiogenic genes through the action of hypoxia inducible factors or HIFs [79,80].…”

“…The involvement of angiogenesis in the progression of CLDs, a condition in which a major general mechanism is represented by chronic activation of wound healing, is not really surprising. In addition, the progressive increase of tissue hypoxia which is detected in the CLD scenario is strictly linked to the histopathological modifications of liver tissue in which the increased deposition of ECM components and formation of fibrotic septa, paralleled by vascular changes, with the time lead to an impairment of the oxygen diffusion and consequent up-regulation of pro-angiogenic pathways [81,82].…”

“…Evidence linking hypoxia and angiogenesis to liver fibrogenesis is now overwhelming and major issues and considerations can be briefly summarized as follows: i) angiogenesis and fibrogenesis have been shown to develop in parallel in human patients, whatever the etiology, as well as in any experimental model of CLD, as indicated by the presence of a high number of endothelial cells and microvascular structures particularly in the portal tracts and, more generally, within fibrotic septa [81][82][83]; ii) experimental and clinical studies also revealed that the expression of VEGF, particularly VEGF-A, is usually detected in hypoxic areas of chronically injured liver, with fibrogenic progression being intrinsically associated with a progressive increase in hypoxic areas in liver parenchyma; iii) in vivo evidence also strongly indicated that VEGF over-expression is strictly associated with hypoxic areas and is mostly limited to hepatocytes as well as to activated HSC/MFs [81,82,84]; MFs are found at close contact with HIF-2α-positive hepatocytes and then are likely to be affected in their behaviour by pro-angiogenic cytokines released by hypoxic hepatocytes. At the same time, MFs themselves are a source of VEGF-A and angiopoietin 1 and express related receptors (VEGFR2, Tie-2) in CLDs [83]; iv) experiments that have compared fibrogenesis progression in HIF-1α liver conditional knock-out mice and related wild type animals, revealed that hypoxia and HIF-1α expression precede fibrosis and that the liver specific silencing of HIF-1α resulted in a significant reduction of liver fibrosis [85]; v) experimental anti-angiogenic therapy, whatever the specific drug or therapeutic strategy employed, resulted in a significant inhibition of fibrogenic progression, being also effective in reducing inflammatory infiltrate, the number of α-SMA positive MFs as well as the increase in portal pressure and, with some drugs, to reduce also formation of porto-systemic collateral vessels and splanchnic vascularization in models of portal hypertensive animals or in cirrhotic animals (reviewed in [81,82,84]).…”

“…At the same time, MFs themselves are a source of VEGF-A and angiopoietin 1 and express related receptors (VEGFR2, Tie-2) in CLDs [83]; iv) experiments that have compared fibrogenesis progression in HIF-1α liver conditional knock-out mice and related wild type animals, revealed that hypoxia and HIF-1α expression precede fibrosis and that the liver specific silencing of HIF-1α resulted in a significant reduction of liver fibrosis [85]; v) experimental anti-angiogenic therapy, whatever the specific drug or therapeutic strategy employed, resulted in a significant inhibition of fibrogenic progression, being also effective in reducing inflammatory infiltrate, the number of α-SMA positive MFs as well as the increase in portal pressure and, with some drugs, to reduce also formation of porto-systemic collateral vessels and splanchnic vascularization in models of portal hypertensive animals or in cirrhotic animals (reviewed in [81,82,84]). …”

“…Experimental studies and a number of studies performed on liver specimens obtained from patients affected by a form of CLDs have also pointed out that hepatic MFs, in particular HSC/MFs, in CLDs are likely to represent a hypoxia-sensitive and cyto-and chemokine-modulated cellular crossroad between critical features like necro-inflammation, pathological angiogenesis and fibrogenesis [81,82,84]. Exhaustive literature has indeed characterized the hypoxia-related profibrogenic and pro-inflammatory role of these cells and major concepts related to the role of hepatic MFs in CLDs angiogenesis may be presented according to their dependence (or not) on hypoxia-related mechanisms.…”