Angiogenesis in chronic liver disease and its complications

Abstract

Nowadays, liver cancer, cirrhosis and other liver-related diseases are the fifth most common cause of mortality in the UK. Furthermore, chronic liver diseases (CLDs) are one of the major causes of death, which are still increasing year-on-year. Therefore, knowledge about the pathophysiology of CLDs and its complications is of uttermost importance. The goal of this review is to clarify the role of angiogenesis in the disease progression of various liver diseases. Looking closer at the pathophysiology of portal hypertension (PH), fibrosis, cirrhosis, non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), we find that angiogenesis is a recurring factor in the disease progression. In PH, several factors involved in its pathogenesis, such as hypoxia, oxidative stress, inflammation and shear stress are potential mediators for the angiogenic response. The progression from fibrosis to cirrhosis, the end-point of CLDs, is distinguished by a prolonged inflammatory and fibrogenic process that leads to an abnormal angioarchitecture distinctive for cirrhosis. In several stages of NASH, a link might be made between the disease progression and hepatic microvasculature changes. HCC is one of the most vascular solid tumours in which angiogenesis plays an important role in its development, progression and metastasis. The close relationship between the progression of CLDs and angiogenesis emphasises the need for anti-angiogenic therapy as a tool for blocking or slowing down the disease progression. The fact that angiogenesis plays a pivotal role in CLDs gives rise to new opportunities for treating CLDs and its complications.

Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture

“…As recently data on the role of neoangiogenesis in NAFLD have emerged, one could hypothesize that these blebs might represent areas of neoangiogenesis (reinforcing the central role of endothelial cells in the altered intrahepatic resistance). 40,41 Their true significance remains currently unclear. The disruption of the regular ordering of blood vessels at the microcirculatory level is likely to be an important static contributor to the intrahepatic resistance, as it can be assumed that blood flow through the chaotic microvascular bed in steatosis is hampered.…”

Mechanisms of adaptation of the hepatic vasculature to the deteriorating conditions of blood circulation in liver cirrhosis

“…Accumulation of HIFs, in particular, HIF1α, increases the VEGF, angiopoietin1 and their receptors expression on activated HSCs. This leads to involvement and sti mulation of SECs, stabilizing the newly formed vessels and providing them with strength [50] . In turn, SECs generate PDGF and TGFβ, helping to attract and migration of HSCs.…”

Portal hypertension-related inflammatory phenotypes: From a vitelline and amniotic point of view

“…Although the final objective of endothelial growth is to form new vessels for oxygen, substrates and blood cells, other functions, like antioxidative as well as antienzymatic stress properties, could be carried out before the new vessels, i.e., mature capillaries, are formed [2,9]. During the evolution of chronic liver diseases the establishment of an abnormal splanchnic and systemic angioarchitecture, including portosystemic collaterals, stand out [2,66,67]. Since in portal hypertension the basic structural alteration found in the gastrointestinal tract is vascular and consists in the increased size and the number of vessels, the very appropriate name of "hypertensive portal intestinal vasculopathy" has been proposed [68].…”