Brief Article
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World J Gastroenterol. Apr 7, 2013; 19(13): 2065-2072
Published online Apr 7, 2013. doi: 10.3748/wjg.v19.i13.2065
Increased endothelin receptor B and G protein coupled kinase-2 in the mesentery of portal hypertensive rats
Qing-Hong Du, Lin Han, Jun-Jie Jiang, Peng-Tao Li, Xin-Yue Wang, Xu Jia
Qing-Hong Du, Lin Han, Jun-Jie Jiang, Peng-Tao Li, Xin-Yue Wang, Xu Jia, Department of Pathology, School of Fundamental Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
Author contributions: Li PT proposed the study; Li PT and Du QH performed research and wrote the first draft; Han L collected and analyzed the data; all authors contributed to the design and interpretation of the study and to further drafts; Li PT is the guarantor.
Supported by Grant from National Key New Drug Creation Project of China, No. 2009ZX09102
Correspondence to: Dr. Peng-Tao Li, Department of Pathology, School of Fundamental Medicine, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China.
Telephone: +86-10-64287015 Fax: +86-10-64287015
Received: October 23, 2012
Revised: January 25, 2013
Accepted: February 5, 2013
Published online: April 7, 2013

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.

Keywords: Portal hypertension, Mesentery, Endothelin, Endothelin B receptor, G protein coupled kinase-2

Core tip: Portal hypertension (PHT) is a life-threatening condition which frequently develops in patients with liver cirrhosis, and has limited treatment options. For many years, endothelin-1 (ET-1) has received considerable interest in the area of liver cirrhosis for its potential contribution to PHT. The aim of the present study was to directly examine the expression of ET-1 and its receptors in the mesentery of rats with PHT, and to clarify how the ET-1 signaling system changed with the development of PHT.