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Beneficial effects of dual vascular endothelial growth factor receptor/fibroblast growth factor receptor inhibitor brivanib alaninate in cirrhotic portal hypertensive rats
Author(s) -
Lin HanChieh,
Huang YiTsau,
Yang YingYing,
Lee PeiChang,
Hwang LihHwa,
Lee WeiPing,
Kuo YingJu,
Lee KueiChuan,
Hsieh YunCheng,
Liu RenShyan
Publication year - 2014
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.12480
Subject(s) - medicine , angiogenesis , vascular endothelial growth factor , fibroblast growth factor , cirrhosis , fibroblast growth factor receptor , angiopoietin receptor , endocrinology , hepatic stellate cell , portal venous pressure , cancer research , portal hypertension , pharmacology , receptor , vegf receptors
Background and Aim Vascular endothelial ( VEGF ) and fibroblast growth factor ( FGF )‐induced hepatic stellate ( HSC s) and liver endothelial cells ( LEC s) activation accelerates hepatic fibrogenesis and angiogenesis, and hemodynamic dysarrangements in cirrhosis. VEGF targeting agents had been reported as potential drugs for cirrhosis. However, the evaluation of effects of dual VEGF / FGF targeting agent in cirrhosis is still limited. Methods Using hemodynamic parameters, blood chemistry, primary isolated HSC s and LEC s, histology, and digital imaging, we assess the effects of 2‐week brivanib alaninate, a dual VEGFR / FGFR inhibitor, treatment in the pathophysiology of bile duct‐ligated‐cirrhotic rats. Results Fibrogenic and angiogenic markers in the serum and liver of bile duct‐ligated‐cirrhotic rats, including hydroxyproline, transforming growth factor‐β1, angiopoietin‐1, VEGF , FGF ‐2, endocan and phosphorylated‐ VEGFR 2/ VEGFR 2, and phosphorylated‐ FGFR / FGFR together with hepatic CD 31/angiopoietin‐1 expressions (immunohistochemistry staining), angiogenesis (micro‐computed tomography scan), microcirculatory dysfunction ( in vivo miscroscopy and in situ liver perfusion study), portal hypertension, and hyperdynamic circulations (colored microsphere methods) were markedly suppressed and ameliorated by brivanib alaninate treatment. In in vitro study, acute brivanib alaninate incubation inhibited the transforming growth factor‐β1‐induced HSC s contraction/migration and VEGF ‐induced LEC s angiogenesis. Concomitantly, the overexpression of various fibrogenic and angiogenic markers in HSC s and LEC s, and in their culture media, was increased in parallel and these changes were suppressed by acute brivanib alaninate incubation. Conclusions This study demonstrated that brivanib alaninate targeting multiple mechanisms and working in the different pathogenic steps of the complications of cirrhotic rats with portal hypertension.