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

Abstract

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.

Adipocyte-Specific Mineralocorticoid Receptor Overexpression in Mice Is Associated With Metabolic Syndrome and Vascular Dysfunction: Role of Redox-Sensitive PKG-1 and Rho Kinase

“…Another study in splanchnic vessels of patients and rats with cirrhosis suggested a role for the ACE2/Ang(1-7)/Mas axis to explain the vascular hypocontractility (35). In our study, Ace2 and Mrga (Mas receptor) gene expression were upregulated in EVAT of Adipo-MROE mice, supporting other studies that have demonstrated hypocontractility (35).…”

“…In Ccl4-induced cirrhotic rats, H 2 O 2 has been directly implicated in regulating mesenteric hypocontractility to noradrenaline through the Rho kinase signaling pathway (34). Another study in splanchnic vessels of patients and rats with cirrhosis suggested a role for the ACE2/Ang(1-7)/Mas axis to explain the vascular hypocontractility (35). In our study, Ace2 and Mrga (Mas receptor) gene expression were upregulated in EVAT of Adipo-MROE mice, supporting other studies that have demonstrated hypocontractility (35).…”

Molecular Mechanisms Leading to Splanchnic Vasodilation in Liver Cirrhosis

“…Other mechanisms have been shown to be involved in activation of the eNOS signaling pathway under this pathological condition, including upregulation of GTP cyclohydrolase I, mediated by bacterial translocation, with production of tetrahydrobiopterin (cofactor of eNOS) [18], phosphorylation of eNOS by Akt [19], and coupling of eNOS with chaperone heat shock protein 90 [20]. Recently, a new mechanism for eNOS modulation in cirrhosis, involving the renin-angiotensin system, was shown [21]. Angiotensin-converting enzyme (ACE) 2 cleaves angiotensin II to generate the vasodilator angiotensin-(1-7), which binds to the receptor Mas (MasR), leading to the activation of eNOS and the endothelial production of NO.…”

Novel rat model of repetitive portal venous embolization mimicking human non-cirrhotic idiopathic portal hypertension

“…Hemodynamic studies were performed under ketamine/xylazine anesthesia (78mg/kg / 12.5mg/kg i.p.) as previously described [14][15][16][17]. Rats were fasted overnight but allowed free access to water.…”

“…Hemodynamics were investigated using the coloured microsphere technique as previously described [14][15][16][17]. The colored microsphere technique was validated by the more frequently used radioactive microsphere method [18].…”