Journal of the American Society of Hypertension
Research articleAblation of angiotensin (1-7) receptor Mas in C57Bl/6 mice causes endothelial dysfunction
Introduction
The Mas gene codes for a G protein-coupled cell surface receptor (GPCR). Although the first attempts to clarify the function of Mas protein characterized it as an angiotensin II (Ang II) receptor,1 our recent studies have shown that Mas binds angiotensin-(1-7) [Ang-(1-7)]2 and is involved in cardiovascular and neuronal regulation. Ang-(1-7) and Mas mainly exert protective effects in the cardiovascular system by reducing blood pressure (BP) and inhibiting cell growth,3, 4, 5, 6, 7 in part by hetero-oligomerization of Mas with the Ang II receptor AT1 and interfering with its signaling.8
The endothelium of blood vessels is an important target for the biological actions of Ang-(1-7).9 Accordingly, Mas expression was found in the endothelial layer of different vessel types such as coronaries and radial and interneural microvessels of the brain10 as well as in the vessels of the corpus cavernosum.11 Association of Mas expression with the endothelium was also shown for cultured endothelial cells derived from human aorta12 and rat cerebral resistance vessels,13 supporting an important role of this GPCR in the function of the endothelium. Sampaio et al12 recently showed that Ang-(1-7) via Mas counteracts Ang II and AT1-dependent c-Src activation and thereby extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and the generation of reactive oxygen species (ROS) by nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase in human endothelial cells. In order to test for the in-vivo relevance of these findings, we recently evaluated endothelial function in Mas gene-deleted mice on the FVB/N background.14 These mice exhibited elevation in BP and impaired endothelial function due to the imbalance between ROS and nitric oxide (NO) metabolism.
It is well known that different mouse strains show completely different responses to cardiovascular interventions such as renal ablation and deoxycorticosterone acetate salt treatment.15, 16 Therefore, in this study we tested whether the endothelial dysfunction observed in Mas-deficient animals is strain specific, by characterizing basal cardiovascular parameters, endothelial function, and NO/ROS metabolism in Mas-deficient mice, backcrossed to C57Bl/6 genetic background.17
Section snippets
Animals, BP Measurement, and Endothelial Function
Local German authorities approved the studies with standards corresponding to those prescribed by the American Physiological Society. Mice were maintained in individually ventilated cages (Tecniplast, Hohenpeissenberg, Germany) under standardized conditions with an artificial 12-hour dark-light cycle, with free access to standard chow (0.25% sodium; SSNIFF Spezialitäten, Soest, Germany) and drinking water ad libitum. All experiments were performed in adult (12 to 16 weeks old) male C57Bl/6Mas
Basal Cardiovascular Parameters and RAS Components in C57Bl/6/Mas-Deficient Mice
To determine the effects of Mas deficiency on regulation of BP, we first characterized basal cardiovascular parameters in Mas-deficient mice on the pure genetic C57Bl/6 background (C57Bl/6Mas−/−)17 by measuring BP in conscious, freely moving animals. Neither MAP nor heart rate was changed in the C57Bl/6Mas−/− mice in comparison to controls (Figures 1A and 1B). To examine the effect of the Mas mutation on main RAS components, we measured PRA and Ang I and II concentrations. None of these
Discussion
The only comprehensive way to study the importance of a gene in a physiological process is to evaluate the effect of its deletion on different genetic backgrounds. Therefore, we have backcrossed Mas-knockout mice22 to two different genetic backgrounds, FVB/N14 and C57Bl/6,17 and evaluated basal cardiovascular parameters and in-vivo endothelial function in these mouse lines.
Whereas in our recent study we have shown that Mas-knockout mice on FVB/N genetic background exhibit elevated BP,14Mas
Conclusion
Taken together, this study and our previous observation in FVB/NMas-deficient mice14 show that ablation of the Ang-(1-7) receptor Mas leads to an imbalance between ROS and NO and to endothelial dysfunction independently of genetic background, providing further evidence for a role of the ACE2/Ang-(1-7)/Mas axis in the regulation of endothelial function.12, 31 However, Mas deficiency has differential effects on the severity of endothelial dysfunction and the BP in two distinct mouse strains.
Acknowledgment
Drs. Luiza A. Rabelo and Ping Xu contributed equally to this work.
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2023, Biochemical PharmacologyCitation Excerpt :The cellular effects of Ang (1–7) are diminished in MAS-KO human endothelial cells, and the vasodilatory function of Ang (1–7) is also lost in aortic rings and mesenteric arteries from Mas-KO mice [82–85]. Apparent endothelial dysfunction in FVB/N Mas-deficient mice suggests a crucial role of the Ang (1–7)-Mas axis in the regulation of endothelial function [86,87]. Interestingly, a phosphoproteomics study showed that Ang (1–7) produces an antiproliferative action in human aortic endothelial cells (HAECs) by activating the downstream FOXO1 transcription factor, a well-known negative regulator of the AKT signaling pathway [88].
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2020, Journal of Sexual MedicineCitation Excerpt :The link between the protective RAS axis and fibrosis is further reinforced by demonstration of increased collagen deposition in corpus cavernosum of Mas-knockout mice. Although this observation has been already made in the previous study in C57BL/6 mice,19 in the current work, we further confirm it using knockout animals generated in a different genetic background (FVB/N), which has been shown to be more suitable for studying the physiological role of the Mas receptor.42 Previously, it has been reported that the Ang-(1-7) peptide is able to inhibit human lung fibroblast differentiation to myofibroblast, while decreasing expression of collagen I, αSMA, and TGF-β1/Smad2/3.43
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2019, Experimental NeurologyAngiotensin (1–7) does not interact directly with MAS1, but can potently antagonize signaling from the AT1 receptor
2018, Cellular SignallingCitation Excerpt :MAS1 deficiency leads to impairment of cardiomyocyte function and deleterious effects on overall cardiac function, accompanied by profibrotic changes [13–15]. MAS1 deficiency was also shown to lead to endothelial dysfunction, vascular resistance and high blood pressure, albeit in a mouse strain-dependent fashion [12, 16, 17]. In contrast, MAS1 deficiency provided protection from salt-induced hypertension [18].
This study was supported by Fapemig/CNPq-Pronex (RASS) and DAAD/CAPES (PROBRAL). Part of the Proceedings of the Vasoactive Peptide Symposium, VII International Vasoactive Peptide Symposium in Ouro Preto, February 14–16, 2008.
Conflict of interest: none.