In:
Journal of Gastroenterology and Hepatology, Wiley, Vol. 29, No. 5 ( 2014-05), p. 1073-1082
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0815-9319
,
1440-1746
DOI:
10.1111/jgh.2014.29.issue-5
Language:
English
Publisher:
Wiley
Publication Date:
2014
detail.hit.zdb_id:
2006782-3
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