Activation of the Mas Receptor by Angiotensin-(1–7) in the Renin–Angiotensin System Mediates Mesenteric Vasodilatation in Cirrhosis

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.