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.