Angiogenesis and Fibrogenesis in Chronic Liver Diseases

Abstract

Pathologic angiogenesis appears to be intrinsically associated with the fibrogenic progression of chronic liver diseases, which eventually leads to the development of cirrhosis and related complications, including hepatocellular carcinoma. Several laboratories have suggested that this association is relevant for chronic liver disease progression, with angiogenesis proposed to sustain fibrogenesis. This minireview offers a synthesis of relevant findings and opinions that have emerged in the last few years relating liver angiogenesis to fibrogenesis. We discuss liver angiogenesis in normal and pathophysiologic conditions with a focus on the role of hypoxia and hypoxia-inducible factors and assess the evidence supporting a clear relationship between angiogenesis and fibrogenesis. A section is dedicated to the critical interactions between liver sinusoidal endothelial cells and either quiescent hepatic stellate cells or myofibroblast-like stellate cells. Finally, we introduce the unusual, dual (profibrogenic and proangiogenic) role of hepatic myofibroblasts and emerging evidence supporting a role for specific mediators like vasohibin and microparticles and microvesicles.

Keywords: ANGPTL3, angiopoietin-like-3 peptide; Akt, protein kinase B; Ang-1, angiopoietin-1; CCL2, chemokine ligand 2; CCR, chemokine receptor; CLD, chronic liver disease; ET-1, endothelin 1; HCC, hepatocellular carcinoma; HIF, hypoxia-inducible factor; HSC, hepatic stellate cell; HSC/MFs, myofibroblast-like cells from activated hepatic stellate cells; Hh, Hedgehog; Hypoxia; LSEC, liver sinusoidal endothelial cell; Liver Angiogenesis; Liver Fibrogenesis; MF, myofibroblast; MP, microparticle; Myofibroblasts; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NO, nitric oxide; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor; VEGF-R2, vascular endothelial growth factor receptor type 2; eNOS, endothelial nitric oxide synthase; α-SMA, α-smooth muscle actin.

Figure 1

Schematic representation of the critical role of activated myofibroblasts (MFs) in the scenario of a progressive chronic liver disease with the direct response to hypoxic conditions and the response to mediators released by other hepatic cell populations (under hypoxia or after chronic injury) or available in the microenvironment and being able to sustain both proangiogenic and profibrogenic role of MFs. Chronic conditions of injury as well as hypoxic conditions operate as efficient events/stimuli able to up-regulate transcription and release of critical proangiogenic mediators (with some also able to sustain fibrogenesis) by hepatocytes, endothelial cells, macrophages, or activated MFs (the latter cells being stimulated to produce proangiogenic cytokines also by leptin). Endogenous vasohibin 1 production is regulated by VEGF in a spatially and temporally coordinated way that operates a negative-feedback loop, driving pathologic angiogenesis through an overall positive effect on activation of HSCs and fibrogenic progression. However, it has been suggested that ectopic overexpression of this antiangiogenic protein (resulting in inhibition of fibrogenesis), being not regulated by VEGF, can disrupt the negative-feedback loop, thus generating constant but lower levels of VEGF synthesis, which are believed to be sufficient to maintain vascular homeostasis but not to sustain pathologic angiogenesis. Green and red arrows in the figure indicate stimulating or inhibitory effects, respectively.