Gastroenterology

Gastroenterology

Volume 145, Issue 4, October 2013, Pages 874-884.e5
Gastroenterology

Original Research
Full Report: Basic and Translational—Liver
Activation of the Mas Receptor by Angiotensin-(1–7) in the Renin–Angiotensin System Mediates Mesenteric Vasodilatation in Cirrhosis

https://doi.org/10.1053/j.gastro.2013.06.036Get rights and content

Background & Aims

Splanchnic vascular hypocontractility with subsequent increased portal venous inflow leads to portal hypertension. Although the renin−angiotensin system contributes to fibrogenesis and increased hepatic resistance in patients with cirrhosis, little is known about its effects in the splanchnic vasculature, particularly those of the alternate system in which angiotensin (Ang) II is cleaved by the Ang-converting enzyme-2 (ACE2) to Ang-(1−7), which activates the G-protein−coupled Mas receptor (MasR). We investigated whether this system contributes to splanchnic vasodilatation and portal hypertension in cirrhosis.

Methods

We measured levels of renin−angiotensin system messenger RNA and proteins in splanchnic vessels from patients and rats with cirrhosis. Production of Ang-(1–7) and splanchnic vascular reactivity to Ang-(1–7) was measured in perfused mesenteric vascular beds from rats after bile-duct ligation. Ang-(1–7) and MasR were blocked in rats with cirrhosis to examine splanchnic vascular hemodynamics and portal pressure response.

Results

Levels of ACE2 and MasR were increased in splanchnic vessels from cirrhotic patients and rats compared with healthy controls. We also observed an ACE2-dependent increase in Ang-(1–7) production. Ang-(1–7) mediated splanchnic vascular hypocontractility in ex vivo splanchnic vessels from rats with cirrhosis (but not control rats) via MasR stimulation. Identical effects were observed in the splanchnic circulation in vivo. MasR blockade reduced portal pressure, indicating that activation of this receptor in splanchnic vasculature promotes portal inflow to contribute to development of portal hypertension. In addition, the splanchnic effects of MasR required nitric oxide. Interestingly, Ang-(1–7) also decreased hepatic resistance.

Conclusions

In the splanchnic vessels of patients and rats with cirrhosis, increased levels of ACE2 appear to increase production of Ang-(1–7), which leads to activation of MasR and splanchnic vasodilatation in rats. This mechanism could cause vascular hypocontractility in patients with cirrhosis, and might be a therapeutic target for portal hypertension.

Section snippets

Human Samples

Experimental procedures to obtain human vessels were approved by the Human Ethics Committee of the University of Bonn 2002/01. During liver transplantation, samples of hepatic arteries from patients with alcohol-induced cirrhosis were obtained (n = 7) and compared with hepatic artery samples from noncirrhotic organ donors, which served as controls (n = 7). Liver samples were obtained from cirrhotic liver explants (n = 8) and compared with healthy liver samples from patients undergoing other

Expression of MasR and ACE2 Is Increased in Splanchnic Vascular Wall in Cirrhotic Rats and Humans

The Ang-(1−7) receptor, MasR, protein was significantly increased in mesenteric arterial vessels from cirrhotic BDL rats (Figure 1A). The findings were similar in human hepatic arteries, where transplant recipient vessels (cirrhotic vessels) contained more MasR protein compared with noncirrhotic donor vessels (control vessels) (Figure 1A).

In contrast, expression of AT1R in splanchnic vessels from cirrhotic animals and cirrhotic patients was not significantly different from control (P = .48 and P

Discussion

This study uncovers a new pathophysiological mechanism of splanchnic vasodilatation, which contributes to portal hypertension in cirrhosis (Figure 7). Our results demonstrate that, in experimental and human cirrhosis, the expression and activity of splanchnic vascular ACE2 are increased. Consequently, local production of the vasodilator and MasR-agonist, Ang-(1−7), is elevated. In addition, locally increased production of Ang-(1−7), together with augmented splanchnic vascular expression of

Acknowledgments

The authors gratefully acknowledge Zhijuan Jia, Gudrun Hack, Silke Bellinghausen, and Stephanie Müller for excellent technical assistance.

References (38)

  • M. Schepke et al.

    Hemodynamic effects of the angiotensin II receptor antagonist irbesartan in patients with cirrhosis and portal hypertension

    Gastroenterology

    (2001)
  • A.J. Macgilchrist et al.

    Plasma noradrenaline in cirrhosis: a study of kinetics and temporal relationship to ascites formation

    Eur J Clin Invest

    (1991)
  • R. Bataller et al.

    Systemic infusion of angiotensin II exacerbates liver fibrosis in bile duct-ligated rats

    Hepatology

    (2005)
  • M. Donoghue et al.

    A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9

    Circ Res

    (2000)
  • M.A. Oliveira et al.

    Synergistic effect of angiotensin-(1−7) on bradykinin arteriolar dilation in vivo

    Peptides

    (1999)
  • J.S. Lubel et al.

    Angiotensin-(1−7), an alternative metabolite of the renin-angiotensin system, is up-regulated in human liver disease and has antifibrotic activity in the bile-duct-ligated rat

    Clin Sci

    (2009)
  • W.W. Vilas-Boas et al.

    Relationship between angiotensin-(1−7) and angiotensin II correlates with hemodynamic changes in human liver cirrhosis

    World J Gastroenterol

    (2009)
  • G. Paizis et al.

    Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2

    Gut

    (2005)
  • D.D. McGregor

    The effect of sympathetic nerve stimulation of vasoconstrictor responses in perfused mesenteric blood vessels of the rat

    J Physiol

    (1965)
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    Author names in bold designate shared co-first authorship.

    Conflicts of interest The authors disclose no conflicts.

    Funding This work was funded in part by a National Health and Medical Research Council of Australia Project Grant and by Deutsche Forschungsgemeinschaft (SFB TRR 57, P18).

    Authors share co-first authorship

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    Authors share co-senior authorship.

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