Increased endothelin receptor B and G protein coupled kinase-2 in the mesentery of portal hypertensive rats.
AIM
To elucidate the mechanisms of mesenteric vasodilation in portal hypertension (PHT), with a focus on endothelin signaling.


METHODS
PHT was induced in rats by common bile duct ligation (CBDL). Portal pressure (PP) was measured directly via catheters placed in the portal vein tract. The level of endothelin-1 (ET-1) in the mesenteric circulation was determined by radioimmunoassay, and the expression of the endothelin A receptor (ETAR) and endothelin B receptor (ETBR) was assessed by immunofluorescence and Western blot. Additionally, expression of G protein coupled kinase-2 (GRK2) and β-arrestin 2, which influence endothelin receptor sensitivity, were also studied by Western blot.


RESULTS
PP of CBDL rats increased significantly (11.89 ± 1.38 mmHg vs 16.34 ± 1.63 mmHg). ET-1 expression decreased in the mesenteric circulation 2 and 4 wk after CBDL. ET-1 levels in the systemic circulation of CBDL rats were increased at 2 wk and decreased at 4 wk. There was no change in ETAR expression in response to CBDL; however, increased expression of ETBR in the endothelial cells of mesenteric arterioles and capillaries was observed. In sham-operated rats, ETBR was mainly expressed in the CD31⁺ endothelial cells of the arterioles. With development of PHT, in addition to the endothelial cells, ETBR expression was noticeably detectable in the SMA⁺ smooth muscle cells of arterioles and in the CD31⁺ capillaries. Following CBDL, increased expression of GRK2 was also found in mesenteric tissue, though there was no change in the level of β-arrestin 2.


CONCLUSION
Decreased levels of ET-1 and increased ETBR expression in the mesenteric circulation following CBDL in rats may underlie mesenteric vasodilation in individuals with PHT. Mechanistically, increased GRK2 expression may lead to desensitization of ETAR, as well as other vasoconstrictors, promoting this vasodilatory effect.
['Du|Qing-Hong|QH|', 'Han|Lin|L|', 'Jiang|Jun-Jie|JJ|', 'Li|Peng-Tao|PT|', 'Wang|Xin-Yue|XY|', 'Jia|Xu|X|']
D000818:Animals D019390:Arrestins D001160:Arterioles D015153:Blotting, Western D002196:Capillaries D004195:Disease Models, Animal D019332:Endothelin-1 D054769:G-Protein-Coupled Receptor Kinase 2 D006975:Hypertension, Portal D008297:Male D008856:Microscopy, Fluorescence D019408:Platelet Endothelial Cell Adhesion Molecule-1 D011312:Pressure D011863:Radioimmunoassay D051381:Rats D017207:Rats, Sprague-Dawley D044022:Receptor, Endothelin A D044023:Receptor, Endothelin B D000071560:beta-Arrestin 2 D000071557:beta-Arrestins
Endothelin G protein coupled kinase-2 Mesentery Portal hypertension Endothelin B receptor