Compared with wild-type animals,

BYL719 ic50 cirrhotic PlGF−/− mice showed a significant reduction in angiogenesis, arteriogenesis, inflammation, fibrosis, and portal hypertension. Importantly, pharmacological inhibition with anti-PlGF antibodies yielded similar results as genetic loss of PlGF. Notably, PlGF treatment of activated hepatic stellate cells induced sustained extracellular signal-regulated kinase 1/2 phosphorylation, as well as chemotaxis and proliferation, indicating a previously unrecognized profibrogenic role of PlGF. Conclusion: PlGF is a disease-candidate gene in liver cirrhosis, and inhibition of PlGF offers a therapeutic alternative with an attractive safety profile. (HEPATOLOGY 2011;) Chronic liver disease can be defined as a complex pathophysiological process of progressive destruction and regeneration of liver parenchyma, leading to fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma. A profound alteration of the hepatic angioarchitecture due to induction of long-term structural vascular changes is underlying this remodeling process. Hepatic angiogenesis occurs

during the progression of several chronic liver diseases, including hepatitis B/C, biliary cirrhosis, alcoholic cirrhosis, and nonalcoholic steatohepatitis. The resulting neovasculature is mainly located in the fibrotic areas of the liver and induces the formation of arterio-portal and porto-venous systemic anastomoses.1 Preclinical studies Wnt pathway of this phenomenon have

demonstrated that angiogenic inhibitors interfere with the progression of fibrosis. In human and experimental liver fibrosis, neovascularization seems to be a process strictly related to progressive fibrogenesis.2 In this context, studies in experimental models of cirrhosis have shown that treatment with angiogenic inhibitors such as neutralizing monoclonal anti–vascular endothelial growth factor receptor (VEGFR) antibody, TNP-470, and adenovirus expressing the extracellular domain of Tie2 decreased liver fibrosis.3, 4 Other parallels between fibrosis and angiogenesis have been postulated, such as the promotion of different subpopulations of hepatic stellate cells (HSCs; angiogenic versus fibrogenic phenotypes), and of hepatic inflammation as a process linking new angiogenesis and fibrogenesis.2, 5 Consequently, multitargeted therapies acting against both angiogenesis and inflammation have been shown to be beneficial in inhibiting the progression of fibrosis to cirrhosis. The validity of the latter approach was demonstrated in cirrhotic rats in which sunitinib and sorafenib, two inhibitors of tyrosine kinase receptors (RTKs) that target the platelet-derived growth factor and vascular endothelial growth factor (VEGF) signaling pathways, produced a reduction in the degree of hepatic angiogenesis, fibrosis, and inflammation, as well as a significant decrease in portal pressure.