title: Cannabinoid receptor 2 agonist ameliorates mesenteric angiogenesis and portosystemic collaterals in cirrhotic rats.
abstract: Angiogenesis in liver cirrhosis leads to splanchnic hyperemia, increased portal inflow, and portosystemic collaterals formation, which may induce lethal complications, such as gastroesophageal variceal hemorrhage and hepatic encephalopathy. Cannabinoids (CBs) inhibit angiogenesis, but the relevant influences in cirrhosis are unknown. In this study, Spraque-Dawley rats received common bile duct ligation (BDL) to induce cirrhosis. BDL rats received vehicle, arachidonyl-2-chloroethylamide (cannabinoid receptor type 1 [CB(1) ] agonist), JWH-015 (cannabinoid receptor type 2 [CB(2) ] agonist), and AM630 (CB(2) antagonist) from days 35 to 42 days after BDL. On the 43rd day, hemodynamics, presence of CB receptors, severity of portosystemic shunting, mesenteric vascular density, vascular endothelial growth factor (VEGF), VEGFR-1, VEGFR-2, phospho-VEGFR-2, cyclooxygenase (COX)-1, COX-2, and endothelial nitric oxide synthase (eNOS) expressions as well as plasma VEGF levels were evaluated. Results showed that CB(1) and CB(2) receptors were present in left adrenal veins of sham rats, splenorenal shunts (the most prominent intra-abdominal shunts) of BDL rats, and mesentery of sham and BDL rats. CB(2) receptor was up-regulated in splenorenal shunts of BDL rats. Both acute and chronic JWH-015 treatment reduced portal pressure and superior mesenteric arterial blood flow. Compared with vehicle, JWH-015 significantly alleviated portosystemic shunting and mesenteric vascular density in BDL rats, but not in sham rats. The concomitant use of JWH-015 and AM630 abolished JWH-015 effects. JWH-133, another CB(2) agonist, mimicked the JWH-015 effects. JWH-015 decreased mesenteric COX-1, COX-2 messenger RNA expressions, and COX-1, COX-2, eNOS protein expressions. Furthermore, JWH-015 decreased intrahepatic angiogenesis and fibrosis.
  
  
  CONCLUSIONS
  CB(2) agonist alleviates portal hypertension (PH), severity of portosystemic collaterals and mesenteric angiogenesis, intrahepatic angiogenesis, and fibrosis in cirrhotic rats. The mechanism is, at least partly, through COX and NOS down-regulation. CBs may be targeted in the control of PH and portosystemic collaterals.
authors.affiliation: Department Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Huang
authors.forename: Sun-Sang
authors.initials: SS
authors.lastname: Wang
authors.forename: I-Fang
authors.initials: IF
authors.lastname: Hsin
authors.forename: Ching-Chih
authors.initials: CC
authors.lastname: Chang
authors.forename: Fa-Yauh
authors.initials: FY
authors.lastname: Lee
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
authors.forename: Chiao-Lin
authors.initials: CL
authors.lastname: Chuang
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Lee
authors.forename: Hsian-Guey
authors.initials: HG
authors.lastname: Hsieh
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D003097:Collateral Circulation / Q000187:drug effects; D003135:Common Bile Duct / Q000601:surgery; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000502:physiology; D006975:Hypertension, Portal / Q000517:prevention & control; D008026:Ligation / Q000379:methods; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology; D008643:Mesentery / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000517:prevention & control*; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors*; D012016:Reference Values; D013152:Splanchnic Circulation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D001095:Arachidonic Acids; D012333:RNA, Messenger; D043885:Receptor, Cannabinoid, CB2; D042461:Vascular Endothelial Growth Factor A; C119325:arachidonyl-2-chloroethylamide