The RAS (renin-angiotensin system) is composed of two arms: the pressor arm containing AngII (angiotensin II)/ACE (angiotensin-converting enzyme)/AT1Rs (AngII type 1 receptors), and the depressor arm represented by Ang-(1-7) [angiotensin-(1-7)]/ACE2/Mas receptors. All of the components of the RAS are present in the brain. Within the brain, Ang-(1-7) contributes to the regulation of BP (blood pressure) by acting at regions that control cardiovascular function such that, when Ang-(1-7) is injected into the nucleus of the solitary tract, caudal ventrolateral medulla, paraventricular nucleus or anterior hypothalamic area, a reduction in BP occurs; however, when injected into the rostral ventrolateral medulla, Ang-(1-7) stimulates an increase in BP. In contrast with AngII, Ang-(1-7) improves baroreflex sensitivity and has an inhibitory neuromodulatory role in hypothalamic noradrenergic neurotransmission. Ang-(1-7) not only exerts effects related to BP regulation, but also acts as a cerebroprotective component of the RAS by reducing cerebral infarct size and neuronal apoptosis. In the present review, we provide an overview of effects elicited by Ang-(1-7) in the brain, which suggest a potential role for Ang-(1-7) in controlling the central development of hypertension.

The MAS1 receptor (R) exerts protective effects in the brain, heart, vessels and kidney. R trafficking plays a critical function in signal termination and propagation and in R resensitization. We examined MAS1R internalization and trafficking upon agonist stimulation and the role of β-arrestin2 in the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt following MAS1R stimulation. Human embryonic kidney 293T cells were transfected with the coding sequence for MAS1R-YFP. MAS1R internalization was evaluated by measuring the MAS1R present in the plasma membrane after agonist stimulation using a ligand-binding assay. MAS1R trafficking was evaluated by its colocalization with trafficking markers. MAS1R internalization was blocked in the presence of shRNAcaveolin-1 and with dominant negatives for Eps15 (a protein involved in endocytosed Rs by clathrin-coated pits (CCP)) and for dynamin. After stimulation, MAS1R colocalized with Rab11, a slow recycling vesicle marker, and not with Rab4, a fast recycling vesicle marker, or LysoTracker, a lysosome marker. Cells transfected with MAS1R showed an increase in Akt and ERK1/2 activation upon Ang-(1-7) stimulation, which was blocked when the CCP pathway was blocked. Suppression of β-arrestin2 by shRNA reduced the Ang-(1-7)-induced ERK1/2 activation, while Akt activation was not modified. We conclude that upon agonist stimulation, MAS1R is internalized through CCP and caveolae in a dynamin-dependent manner and is then slowly recycled back to the plasma membrane. MAS1R induced Akt and ERK1/2 activation from early endosomes, and the activation of ERK1/2 was mediated by β-arrestin2. Thus, MAS1R activity and density may be tightly controlled by the cell.