title: Beneficial effects of dual vascular endothelial growth factor receptor/fibroblast growth factor receptor inhibitor brivanib alaninate in cirrhotic portal hypertensive rats.
abstract: OBJECTIVE
  Vascular endothelial (VEGF) and fibroblast growth factor (FGF)-induced hepatic stellate (HSCs) and liver endothelial cells (LECs) 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 HSCs and LECs, 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-VEGFR2/VEGFR2, and phosphorylated-FGFR/FGFR together with hepatic CD31/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 HSCs contraction/migration and VEGF-induced LECs angiogenesis. Concomitantly, the overexpression of various fibrogenic and angiogenic markers in HSCs and LECs, 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.
authors: Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors: Han-Chieh
authors: HC
authors: Lin
authors: Yi-Tsau
authors: YT
authors: Huang
authors: Ying-Ying
authors: YY
authors: Yang
authors: Pei-Chang
authors: PC
authors: Lee
authors: Lih-Hwa
authors: LH
authors: Hwang
authors: Wei-Ping
authors: WP
authors: Lee
authors: Ying-Ju
authors: YJ
authors: Kuo
authors: Kuei-Chuan
authors: KC
authors: Lee
authors: Yun-Cheng
authors: YC
authors: Hsieh
authors: Ren-Shyan
authors: RS
authors: Liu
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000235:genetics*; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D058990:Molecular Targeted Therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D014227:Triazines; C509922:brivanib; D040262:Receptors, Vascular Endothelial Growth Factor; D000409:Alanine
keywords: brivinab alaninate; hyperdynamic circulations; microcirculatory dysfunction; portal hypertension