Portal hypertension, the most important complication in patients with
cirrhosis of the liver, is a serious and life-threatening disease for which there are few therapeutic options. Because angiogenesis is a pathological hallmark of
portal hypertension, the goal of this study was to determine the effects of
sorafenib-a potent inhibitor of proangiogenic
vascular endothelial growth factor receptor 2 (VEGFR-2),
platelet-derived growth factor receptor beta (PDGFR-beta), and
Raf kinases-on splanchnic, intrahepatic, systemic, and portosystemic collateral circulations in two different experimental models of
portal hypertension: rats with prehepatic
portal hypertension induced by partial portal vein
ligation and rats with intrahepatic
portal hypertension and
secondary biliary cirrhosis induced by bile duct
ligation. Such a comprehensive approach is necessary for any translational research directed toward defining the efficacy and potential clinical application of new therapeutic agents.
Sorafenib administered orally once a day for 2 weeks in experimental models of
portal hypertension and
cirrhosis effectively inhibited
VEGF, PDGF, and Raf signaling pathways, and produced several protective effects by inducing an approximately 80% decrease in splanchnic neovascularization and a marked attenuation of hyperdynamic splanchnic and systemic circulations, as well as a significant 18% decrease in the extent of portosystemic collaterals. In cirrhotic rats,
sorafenib treatment also resulted in a 25% reduction in portal pressure, as well as a remarkable improvement in liver damage and intrahepatic
fibrosis,
inflammation, and angiogenesis. Notably, beneficial effects of
sorafenib against tissue damage and
inflammation were also observed in splanchnic organs.
CONCLUSION: Taking into account the limitations of translating animal study results into humans, we believe that our findings will stimulate consideration of
sorafenib as an effective therapeutic agent in patients suffering from advanced
portal hypertension.