title: Endothelin receptor blockers reduce shunting and angiogenesis in cirrhotic rats.
abstract: BACKGROUND
  Angiogenesis plays a pivotal role in splanchnic hyperaemia and portosystemic collateral formation in cirrhosis. Endothelin-1 (ET-1), an endothelium-derived vasoconstrictor, has also been implicated in the pathogenesis of cirrhosis and portal hypertension.
  
  
  METHODS
  This study aimed to survey the influences of ET-1 in cirrhosis-related angiogenesis. Common bile duct ligation was performed on Spraque-Dawley rats to induce cirrhosis. Since the 14th day after the operation, rats randomly received distilled water (DW, control), bosentan [a nonselective ET receptor (ETR) blocker] or ambrisentan (a selective ETA R blocker) for 4 weeks. On the 43rd day, portal and systemic haemodynamics, liver biochemistry, portosystemic shunting degree, mesenteric vascular density, mRNA and/or protein expressions of relevant angiogenic factors were evaluated.
  
  
  RESULTS
  In cirrhotic rats, bosentan significantly reduced portal pressure. Ambrisentan did not influence haemodynamics and liver biochemistry. Both of them significantly improved the severity of portosystemic collaterals and decreased the mesenteric vascular density. Compared with the DW-treated cirrhotic rats, splenorenal shunt and mesenteric inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), vascular endothelial growth factor mRNA expressions and mesenteric iNOS, COX2, VEGF, phospho-VEGF receptor 2, Akt and phospho-Akt protein expressions were down-regulated in both groups.
  
  
  CONCLUSIONS
  In rats with liver cirrhosis, both nonselective and selective ETA R blockade ameliorate the severity of portosystemic shunting and mesenteric angiogenesis via the down-regulation of VEGF pathway and relevant angiogenic factors. ET receptors may be targeted to control the severity of portosystemic collaterals and associated complications in cirrhosis.
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of Gastroenterologyand Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shao-Jung
authors.initials: SJ
authors.lastname: Hsu
authors.affiliation: Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Te-Yueh
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Department of Medical Affair and Planning, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Sun-Sang
authors.initials: SS
authors.lastname: Wang
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chiao-Lin
authors.initials: CL
authors.lastname: Chuang
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of Gastroenterologyand Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Fa-Yauh
authors.initials: FY
authors.lastname: Lee
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of Gastroenterologyand Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.|Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Huang
authors.affiliation: Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: I-Fang
authors.initials: IF
authors.lastname: Hsin
authors.affiliation: Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of Gastroenterologyand Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan.
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
mesh_terms: D000818:Animals; D000077300:Bosentan; D003097:Collateral Circulation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology; D006975:Hypertension, Portal; D008103:Liver Cirrhosis; D008297:Male; D009389:Neovascularization, Pathologic; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism; D010666:Phenylpropionates / Q000494:pharmacology*; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D017082:Portal Pressure / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects / Q000378:metabolism
chemical_list: D065130:Endothelin A Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D010666:Phenylpropionates; D010750:Phosphoproteins; D011724:Pyridazines; D012333:RNA, Messenger; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; C000602029:Kdr protein, rat; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; C467894:ambrisentan; D000077300:Bosentan
keywords: Angiogenesis; endothelin-1; liver cirrhosis; portosystemic collaterals; vascular endothelial growth factor