• Beta-arrestin;
  • cirrhosis;
  • hyperdynamic circulation;
  • portal hypertension;
  • Rho kinase;
  • vascular hypocontractility


Background  Portal hypertension is triggered by vasodilation due to impaired contraction of extrahepatic vessels. Angiotensin II type 1 (AT1) receptor-induced vasocontraction is mediated by G proteins and may be desensitized by recruitment of β-arrestin-2 to the receptor. In this study, we analysed the interaction of AT1 receptors with β-arrestin-2 in the context of vascular hypocontractility in rats with CCl4-induced cirrhosis.

Methods  Micronodular liver cirrhosis in rats (= 15) was induced by regular CCl4 exposure. Age-matched rats (n = 15) served as controls. Contractility of aortic rings was measured by myography. Protein expressions and phosphorylations were assessed by Western blot analysis, and AT1 receptor interaction with β-arrestin-2 by co-immunoprecipitation.

Results  Aortic rings from CCl4 rats were hypocontractile to angiotensin II independent of nitric oxide synthases (Nω-nitro-l-arginine methyl ester 200 μM). Expression of the AT1 receptor, Gαq/11 and the contraction-mediating effector Rho kinase was similar in aortas from both groups. Expression and AT1 receptor binding of β-arrestin-2 were up-regulated in aortas from CCl4 rats. Stimulation of isolated aortas with exogenous angiotensin II caused recruitment of β-arrestin-2 in aortas from noncirrhotic rats, but no further interaction of AT1 receptors with β-arrestin-2 was found in aortas from CCl4 rats. While angiotensin II stimulation resulted in Rho kinase activation in aortas from noncirrhotic rats but not in aortas from CCl4 rats, extracellular signal-regulated kinase activation in response to angiotensin II was observed in aortas from both groups.

Conclusions  Vascular hyporesponsiveness to angiotensin II in CCl4 rats is due to enhanced interaction of the AT1 receptor with β-arrestin-2 and consecutively changed receptor function.