Mas1 Receptor Knockout Rats as a Novel Model to Study Vascular Function in Salt‐Sensitive Hypertension

Abstract

Hypertension is a critical risk factor for coronary and peripheral arterial disease, stroke and heart failure. It has been shown that activation of the Mas1 receptor (Mas1R) for angiotensin (1–7) [Ang (1–7)] has potent beneficial effects to offset the impaired vascular relaxation caused by increased oxidative stress, reduced nitric oxide (NO) availability, and down regulation of antioxidant defense mechanisms that occur during salt‐induced angiotensin II (ANG II) suppression. The recent development of a Mas 1R‐knockout rat (Mas 1R KO) in the Dahl salt sensitive (SS) genetic background is a crucial development, because this genetic model will allow for more detailed studies of Mas 1R function at the whole animal, molecular, and cellular level in salt‐sensitive rats. The aim of this study was to provide initial phenotyping of vascular responses in middle cerebral arteries (MCA) of wild type (WT) and Mas1R KO rats. Mas 1R KO− and WT rats were maintained on a low salt (LS; 0.4 % NaCl) diet to evaluate endothelial function without elevated blood pressure. MCA were isolated to assess vascular function ex vivo using the endothelium‐dependent vasodilator acetylcholine (ACh), exogenously added Ang (1–7), the non‐peptide Ang‐(1–7) mimic AVE 0991, and the NO donor sodium nitroprusside (SNP). ACh induced a concentration‐dependent dilation in isolated arteries from Mas 1R WT rats but not in Mas 1R KO arteries (p<0.05). Arteries stimulated with Ang (1–7) and AVE 0991 exhibited a concentration‐dependent vasodilation in Mas 1R WT but not in Mas 1R KO rats. However, endothelium‐independent vessel relaxation by SNP was unaltered in KO vessels compared to WT controls. The vasodilator effect of Ang (1–7) and AVE 0991 were eliminated by the Ang (1–7) receptor antagonist A779 and by inhibition of NO synthase with L‐NAME. Dilation of MCA in response to the AT2 receptor agonist cGP42112A was unaltered in Mas 1R KO rats. Our results indicate that Mas 1R activation has an important role in maintaining endothelial cell function in WT rats. Use of the novel Mas 1R KO genetic rat model provides a powerful tool to investigate Mas 1R functions at the molecular and cellular level. Further study of the mechanisms by which Mas1 receptors induce protective effects in the endothelium will be important since Mas 1R receptor analogs such as AVE 0991 and Ang (1–7) may offer a potentially novel therapeutic strategy for the management of hypertension.Support or Funding InformationThis work was supported in part by grants: R21‐OD024781‐01, R01‐HL128242 and T32‐GM089586 from the National Institutes of Health, Bethesda, MDThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.