The renin-angiotensin system (RAS) constitutes one of the most important systems in the control of the cardiovascular function. The RAS is a key regulator of blood pressure and electrolyte homeostasis. RAS cascade begins with the secretion of renin from the juxtaglomerular cells into the circulation, which triggers the systemic production of a pressor peptide, angiotensin (Ang) II [1]. The hepatocytes synthesize and release angiotensinogen (AGT) into the circulation, which contains at its N-terminal end the decapeptide Ang I that is released by the interaction of AGT with circulating renin [2]. The angiotensin converting enzyme (ACE) is a dipeptidyl carboxypeptidase that catalyzes the hydrolysis of Ang I into Ang II [3]. For many years, Ang II has been considered the main bioactive component of the RAS. However, the existence of many other biologically active RAS components has currently been recognized, with similar, opposite, or distinct effects compared to Ang II. Generation of the different components of the RAS is presented in Figure 1. Ang-(1-12) is a 12 amino acid peptide present in plasma, heart, kidney and other tissues and derived from AGT from a renin-independent cleavage, as a precursor for Ang II formation independent from renin action. Like Ang II, Ang-(1-12) exerts a systemic pressor response [4]. Ang III is a biologically active peptide with similar actions to those of Ang II, formed from Ang II by the action of aminopeptidase A [5]. Ang A is an octapeptide derived from Ang II with an amino acid sequence that differs from Ang II only in the first amino acid: alanine instead of aspartic [6]. Like Ang II, Ang-(1-12), Ang III and Ang A cause vasoconstriction and smooth muscle cell proliferation by activation of Ang II type 1 receptor (AT1R) [7–9]. At the peripheral level, Ang III induces natriuresis and diuresis by acting on Ang II type 2 receptor (AT2R) [10].

Other peptides like Ang IV, Ang-(1-7), Ang-(1-9) and alamandine exert protective effects opposite to those displayed by Ang II. Ang IV is synthetized from Ang III by the action of aminopeptidase N and can be generated from Ang II by the activity of aminopeptidase D [11]. Ang-(1-7) is a peptide formed by seven amino acids that lacks the phenylalanine residue at position 8 of the Ang II sequence. Ang-(1-7) can be formed from Ang I through the enzymatic activity of neutral endopeptidase (NEP), prolylendopeptidase, and thimet oligopeptidase, from Ang-(1-9) by ACE or NEP or from Ang II by an enzyme homologous to ACE named ACE2 [12]. ACE2 also acts on Ang I, although with an enzymatic efficiency 400 times lower, generating Ang-(1-9), which can be cleaved to Ang-(1-7) by ACE or NEP [13]. Both Ang-(1-7) and Ang II can, in turn, be generated from AGT through a renin-independent pathway, from Ang-(1-12) [12]. Alamandine is a heptapeptide that can be originated from Ang-(1-7) by decarboxylation at the N-terminal aspartic residue through an unknown yet enzymatic pathway or from Ang A by the action of ACE2 [14]. ACE2 is a multifaceted enzyme that negatively regulates systemic and local RAS function. Besides the generation of Ang-(1-7), ACE2 limits the production of Ang II and can act on other vasoactive peptides with important functions in the regulation of blood pressure, such as apelin or dynorphin [15]. ACE2 also participates in the signaling mediated by integrins in human hearts [16] and functions as the key receptor of severe acute respiratory syndrome (SARS) coronavirus [17]. Thus, ACE2 is implicated in the regulation of lung, cerebral, cardiovascular and renal function. Recently, ACE2 has gain a lot of attention, since this enzyme is the functional receptor for SARS-CoV-2, the etiological agent of coronavirus disease 2019 (COVID-19) [18].

The actual view is to consider the RAS as a system constituted by two opposite arms. The pressor arm is composed by Ang II and the AT1R, which mediates the vasoconstrictor, proliferative, hypertensive, oxidative, pro-inflammatory and profibrotic effects of the RAS [19]. The depressor arm of the RAS is mainly composed by Ang-(1-7), its receptor Mas (MasR) which acts as a mediator of the depressor, vasodilatory, antiproliferative, antioxidant, anti-inflammatory and antifibrotic effects of Ang-(1-7) and the AT2R, which opposes the effects mediated by AT1R activation [20]. The first evidence showing that Ang-(1-7) is the physiological agonist of MasR was based on the loss of intracellular signaling and effects of Ang-(1-7) and the reduced Ang-(1-7) binding to kidney sections in mice with genetic deletion of MasR [21]. Binding studies in Mas-transfected CHO cells demonstrated high affinity and specific binding of Ang-(1-7), which was not modified by an AT1R or AT2R antagonist, thus excluding Ang-(1-7) binding to these receptors [21]. It was recently reported that MasR is not an Ang-(1-7) receptor because Ang-(1-7) binding, which was performed with Ang-(1-7) labelled with a mixture of ¹²⁵I: ¹²⁷I (1:19), was not specific in tissue membrane preparations [22]. However, since the authors did not evaluate competitive binding in the presence of A-779 (MasR antagonist) [22], Ang-(1-7) specific binding to MasR cannot be excluded under these experimental conditions. In contrast, unpublished results from our lab (manuscript under preparation) showed that the specific ¹²⁵I-Ang-(1-7) binding to - macrophages from a human monocytic leukemia cell line (THP-1) was specific with a Kd value around 250 nmol/L, demonstrating that at least in these cells MasR is a specific receptor for Ang-(1-7).

There is substantial evidence showing the existence of tissue RAS at renal, cardiac, adipose, arterial wall and cerebral level, among others, which are independently regulated from the systemic RAS [23]. According to Sigmund et al. [23], data supporting the existence of a RAS system in the brain can be classified into two categories. The first category is represented by evidence showing that all components of the RAS are synthesized de novo in the brain. All RAS essential constituents have been detected in the brain, including the substrates and enzymes necessary for the synthesis and metabolism of the different Angs as well as their specific receptors [24]. The second category is represented by evidence demonstrating the physiological functions of the central RAS. The brain RAS is a key regulator of blood pressure and electrolyte homeostasis and exerts a critical role in the development of the nervous system and cognitive processes [12, 19, 25]. The brain RAS is also involved in the pathogenesis of neurogenic hypertension and in the development of neurological disorders such as Alzheimer’s disease (AD), stroke, anxiety, depression and emotional stress [25–29].

Regarding the protector axis of the RAS, all its components have been detected in almost all cells of the brain (see the following section). Although there is extensive evidence showing the presence and functionality of central RAS in almost every species, it has been proposed that independent Ang generation in the brain is unlikely. Uijl et al. [30] could not detect renin levels that supported brain local synthesis. Van Thiel et al. [31] showed that Ang I was undetectable in brains of spontaneously hypertensive rats (SHRs), suggesting that there is no local Ang I production in the brain. The authors concluded that brain Ang II represents Ang II taken up from blood rather than locally generated Ang II. Circulating Ang II may gain access following situations where the blood-brain barrier (BBB) is disrupted, such as hypertension [32]. The biochemical and functional complexity of the RAS at central level, as well as the fact that the same detection methods applicable to the peripheral circulating system may not be applicable to the RAS in the brain may have contributed to originate this controversy.

The present review is focused on the expression of the brain Ang-(1-7)/MasR axis, its main cerebral effects and the evidence regarding its involvement in the pathophysiology of several diseases.

Unlike other tissues, the access of the peripheral RAS components to many of the brain regions is limited by the BBB. The existence of a BBB prevents, under physiological conditions, that circulating components of the RAS, including renin and Ang II, reach most of the brain areas, except for the circumventricular organs [33]. The RAS is present in different cell types within the brain, such as neurons, microglia, astrocytes and oligodendrocytes. The existence of an intracellular RAS with intracrine or autocrine functions has been widely described [34, 35]. Neurons present an intracellular RAS, mainly involving the mitochondria, nucleus and neurosecretory vesicles [35, 36].

Currently, only a limited array of methodologies is available to quantify Ang peptides at physiological concentrations [37]. For years, enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) have been the most used biochemical methods to quantify endogenous peptides [38]. One concern that arise when using these methodologies is antibody specificity, since Ang peptides in the RAS only differ by one or two amino acids, which can lead to cross-reactivity. This limitation in antibody specificity has raised the need to validate each antibody [39]. Over the last years, mass spectrometry (MS) has arisen as an important alternative for the development of assays designed to specifically identify Ang peptides [40]. More recently, a new technology was developed by coupling a laboratory-built capillary electrophoresis nanoelectrospray ionization platform to a high-resolution mass spectrometer, allowing the quantification of Ang peptides with high sensitivity [37].

The quantification of Ang-(1-7) and Ang II is challenging since endogenous levels of these peptides are quite low (concentrations in the fmol per gram or fmol per milliliter range) [38]. There is large discrepancy in the levels of Ang II and Ang-(1-7) reported in the literature. The differences found in Ang levels may be due to lack of proper standardization of the techniques used to obtain and process the samples, to extract and/or to measure Ang peptides in different tissues and in circulation. Most studies have reported human and animal plasma concentrations of Ang-(1-7) in the pmol/L range [41–44]. Using RIA-HPLC or HPLC-MS, Ang II and Ang-(1-7) were identified and quantified in the brain, with values in the fmol/g range [38, 42, 45–47]. Transgenic mice with elevated brain Ang II in the brain develop hypertension, highlighting the pathophysiological relevance of this local production of Ang II [48]. It has been proposed that Ang II may access to the brain under conditions where the BBB is partially disrupted, such as hypertension [30, 32]. Supporting this, Van Thiel et al. [31] showed that Ang I was undetectable by MS in brains of SHRs, suggesting that there is no local Ang I production in the brain. In this sense, the source of brain Ang II could be represented by circulating Ang II that binds to brain Ang receptors in conditions where the BBB integrity is compromised, such as deoxycorticosterone acetate (DOCA)-salt hypertension. It has been shown that DOCA-salt suppressed plasma and brain Ang II in parallel, while spironolactone simultaneously increased Ang II and lowered blood pressure, indicating that DOCA-salt hypertension is not mediated by brain RAS activation [49]. Contrary to this hypothesis, we have shown that Ang II levels were increased in brainstem neurons from SHRs compared with those from WKY animals. As this work was done using primary culture of neurons from brainstem, Ang II source could not be represented by circulating Ang II, since there was no blood [36].

The majority of Ang II central effects are mediated by the activation of AT1R [35]. AT1R is expressed in areas of the brain implicated in blood pressure control including the rostroventrolateral medulla (RVLM), caudoventrolateral medulla (CVLM), the nucleus of the solitary tract (NTS), the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) of the hypothalamus [50]. AT1R hyperactivation exerts important actions in the promotion of vasoconstriction within the brain, exacerbating cognitive impairment, cell death and inflammation [34]. For further reading on Ang II and Ang receptors please refer to the reviews by Forrester et al. [19], Abiodun and Ola [26], Miller and Arnold [51], Cosarderelioglu et al. [29] and Ren et al. [32], since this review is focused on the expression and regulation of the Ang-(1-7)/MasR axis in the brain.

Central Ang-(1-7) acts at sites involved in the control of the cardiovascular function, mainly in regions associated to tonic and reflex regulation of blood pressure, like the hypothalamic nuclei and the dorsomedial and ventrolateral medulla. Central overexpression of Ang-(1-7) has been shown to induce predominantly parasympathetic cardiovascular effects, while blockade of the RAS depressor axis by administration of A-779, a specific MasR antagonist, predominantly promotes sympathetic responses [80]. Therefore, the Ang-(1-7)/MasR axis has a fundamental role in autonomic modulation [80].

Injection of Ang-(1-7) in the NTS, CVLM, and PVN or in the anterior hypothalamic area induces a reduction in arterial pressure [12]. The hypotensive effect of Ang-(1-7) in the hypothalamus and in the CVLM is dependent on the generation of nitric oxide (NO) [81, 82]. At this localization, cardiovascular effects of Ang-(1-7) are blocked by A-779, evidencing that brain Ang-(1-7) effects are associated to MasR activation [83]. On the contrary, the injection of Ang-(1-7) in the RVLM induces a rise in arterial pressure and this effect is mediated by the generation of superoxide anion [84].

Intracerebroventricular (ICV) Ang-(1-7) infusion for 4 days induced enhancement of the baroreflex control of the sympathetic activity at renal level [85]. This effect was similarly seen in transgenic mice with human ACE2 overexpression in the brain [86]. Central administration of Ang-(1-7) induces a reduction of blood pressure in hypertensive rats. Long-term infusion (14–28 days) of Ang-(1-7) induced a reduction in the increased arterial pressure in DOCA-salt rats [87], TGR(mREN2)L-27 hypertensive rats [88] and Ang II induced hypertensive rats [89]. Accordingly, increased ACE2 selective overexpression in the RVLM or PVN reduced high arterial pressure in SHR [90] and Ang II induced-hypertensive rats [86], respectively.

The activation of MasR by Ang-(1-7) at central level is not only related to the regulation of the cardiovascular function. It has been shown that Ang-(1-7), through MasR, stimulates synaptic plasticity in rat hippocampus [91] and lateral amygdala, participating in the processes of learning and memory [92]. Ang-(1-7)/MasR axis stimulation is associated to neuroprotection. Ang-(1-7) through MasR stimulation elicits phospholipase A2 activation, arachidonic acid release and NO generation [12]. The Ang-(1-7)/MasR axis is also linked to stimulation of phosphatidylinositol 3-kinase/Akt, mitogen-activated protein kinase and protein kinase A (PKA) pathways [92]. Increased levels of NO, arachidonic acid and activation of the signaling pathways elicited by Ang-(1-7) promote neuronal survival [36]. The activation of the protective axis of the RAS has beneficial effects through improvements in the cerebral oxidative state and inflammation through the inhibition of brain nuclear factor-κB (NF-κB) [93]. The neuroprotector effects of Ang-(1-7)/MasR in cerebral ischemia are associated to a pro-angiogenic effect [69]. Ang-(1-7) also increases cerebral blood flow, which contributes to its neuroprotective effects [69]. The main mechanisms and signaling pathways implicated in the neuroprotection proposed for ACE2/Ang-(1-7)/MasR are presented in Figure 2.

The existence of a close interaction between the RAS and other brain systems like dopaminergic, cholinergic and adrenergic systems has also been shown [34]. By interacting with other neurotransmitters, Ang-(1-7) might be involved in numerous brain processes, such as hormone synthesis, motor function and cognition. It has been shown that Ang-(1-7) influences the release of norepinephrine (NE), gamma aminobutyric acid (GABA), glutamate, substance P and dopamine at different regions of the brain, affecting in this way the effects elicited by these neurotransmitters [94–98].

Ang-(1-7) central effects on the regulation of cardiovascular function are related to variations in synaptic concentrations of NE. Ang-(1-7), counteracting Ang II effects, exhibits a sympathoinhibitory action [98]. Ang-(1-7) promotes a reduction in synaptic NE levels in neurons of the hypothalamus and brainstem of normotensive and SHRs. This effect is the result of a reduction in the release and synthesis of NE and a rise in its uptake by neurons [99]. Ang-(1-7) inhibition of NE release is mediated through NO generation by cyclic guanosine monophosphate/protein kinase G stimulation [100]. Besides inhibiting the release of NE, Ang-(1-7) reduces the protein expression of tyrosine hydroxylase, the enzyme that catalyzes the rate limiting step in the synthesis of catecholamines, by stimulating its degradation via ubiquitin-proteasome in hypothalamic neurons of normotensive and SHRs [78]. Ang-(1-7) also acts as a long-term stimulus to increase NE neuronal uptake. This effect is exerted by inducing the increase in the transcription and protein content of the NE transporter [79], which regulates NE levels in the synaptic cleft [101]. Ang-(1-7) stimulation of neuronal NE uptake is mediated by a mechanism dependent on Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) activation [78]. It has been suggested that Ang-(1-7) could participate in the central motor control because it regulates the secretion of dopamine and GABA in the dorsal striatum [79]. Dopaminergic neurons exhibit a downregulation of the Ang-(1-7)/MasR axis with aging which could promote the aging-related vulnerability to neurodegeneration [66]. Brain Ang-(1-7) has also been linked to emotional stress and anxiety modulation [102]. MasR activation might be involved in these Ang-(1-7) induced actions, since knock out mice for MasR exhibited increased anxiety behavior [103]. On the other hand, central administration of Ang-(1-7) attenuated anxiety in rats with low brain AGT [104].

Central Ang-(1-7) effects are summarized in Table 1.

As previously mentioned, the Ang-(1-7)/MasR axis of the RAS has been found in various areas of the brain associated with the cardiovascular function like NTS, CVLM, RVLM and PVN of the hypothalamus [12]. In addition, MasR has been detected in autonomic preganglionic neurons, ganglia and terminals of the nerves [118], involved in neuromodulatory actions that can directly influence blood pressure control [102]. Chronically central Ang-(1-7) infusion decreases blood pressure in animal models of hypertension [119]. Ang-(1-7) ICV administration for 14 days reduced arterial pressure in transgenic hypertensive rats (mRen2)27 [88]. Ang-(1-7) also stabilized the baroreflex control of heart rate, reestablished cardiac autonomic balance, prevented cardiac hypertrophy, and reduced the altered ratio of Ang II/Ang-(1-7) in the heart [88]. Most of those actions were mediated by MasR, given the fact that they were abolished by its antagonist, A-779. Ang-(1-7) chronic ICV administration for 14 days also reduced the high blood pressure levels in DOCA-salt rats [87]. Central administration of Ang-(1-7) lowered arterial pressure levels, improved baroreflex bradycardia sensitivity indexes, restored the balance of cardiac autonomic tone and returned the levels of left ventricular mRNA expression of collagen type I to normal ones [87]. The augmentation of Ang-(1-7) levels in the brain chronically also induced beneficial cardiometabolic effects in rats fed a high fructose diet [120]. ICV administration of Ang-(1-7) for 4 weeks decreased cardiac sympathetic tone, stabilized blood pressure levels and restored baroreflex sensitivity. Ang-(1-7) also improved metabolic parameters like glucose and insulin levels, and improved glucose tolerance in rats with fructose overload. Ang-(1-7) chronic administration also diminished mRNA expression of neuronal nitric oxide synthase in hypothalamus and dorsomedial medulla [120]. ICV infusion of the MasR selective antagonist A-779 in female rats with aldosterone/NaCl induced hypertension aggravated the rise in blood pressure evidencing the considerable protective effects of Ang-(1-7) synthesized endogenously in situations of high blood pressure [89].

Ang-(1-7) administration into the basolateral amygdala in normotensive rats decreased the tachycardia and prevented the rise of arterial pressure provoked by acute emotional stress [121]. These actions were totally blocked by A-779, demonstrating the participation of MasR [121]. In contrast, Ang-(1-7) administration in the RVLM increased sympathetic nerve activity at renal level and the arterial pressure in two-kidney, one clip (2K1C)-operated rats [122]. Ang-(1-7) was also associated to enhanced cardiac sympathetic afferent reflex and sympathetic output in these rats by activation of MasR [122]. Ang-(1-7) administration in RVLM also increased blood pressure in animals with stress-induced hypertension, without differences in blood pressure levels in those animals in relation to their respective normotensive controls [123].

It must be pointed out that amounts of administered Ang-(1-7) exceed, by orders of magnitude, the expected concentrations of this peptide in tissues or in the blood. One reason to use a high concentration of Ang-(1-7) in pre-clinical studies is the short half-life of this peptide [124], as a way to assure that they reach the receptors in amount enough to measure a response. Using MS, we previously showed that Ang-(1-7) is degraded in hypothalamic and brainstem neurons from rats [78].

Ang-(1-7) effects in animal models of cardiovascular disease are summarized in Table 2.

G protein-coupled receptor (GPCR) can trigger signaling pathways at dynamic nanodomains localized both on the cell membrane and on membranes of intracellular compartments. Lateral diffusion and trafficking influence the place where GPCRs are located within the nanodomains, thus modulating in this way the timing and place of GPCR signaling [154, 155]. Trafficking of GPCR provides distinct signaling platforms critical for specifying receptor function. Upon agonist stimulation most GPCRs are internalized into early endosomes, from where they can activate others signaling pathways, leading in this way to biological responses different from those induced from the plasma membrane. Thus, GPCRs can have differential signaling consequences depending on their subcellular localization [156]. Once internalized, GPCR may be recycled back to the cellular membrane, be directed to lysosomes for degradation or be translocated to other organelles, like the nucleus or mitochondria [155, 157]. MasR belongs to GPCR family [12]. After being stimulated with Ang-(1-7), MasR is internalized into early endosome. MasR induces Akt and ERK1/2 activation from early endosomes, and then it returns to the plasma membrane via slow recycling vesicles in MasR-expressing HEK293T cells [158]. This way of internalization was also detected in brainstem neurons from normotensive Wistar-Kyoto rats [36]. However, in brainstem neurons from SHR, MasR shows a differential trafficking: the proportion of MasRs that were internalized into early endosomes was increased and the proportion of MasRs recycled back to the plasma membrane was reduced in SHR compared to WKY brainstem neurons. Surprisingly, in SHR neurons but not in WKY neurons, Ang-(1-7) promoted MasR translocation to the nucleus [36]. Up to now there is no evidence about the biological response induced by MasR translocation to the nucleus of neurons from SHR.

Most of GPCRs display changes in its functionality due to interaction with other receptors [159]. MasR has been shown to heteromerize with AT1R, reducing the synthesis of inositol phosphates and utilization of intracellular calcium stimulated by Ang II [160]. MasR-AT2R heteromerization induced CX3CR1 mRNA expression in cultured astrocytes from mice [161] and an increase in NO generation as well as diuretic and natriuretic responses in obese Zucker rat kidney [162]. In addition, MasR-B2R interaction was associated to a delay in sequestration of MasR from the cell membrane and to an increased affinity ligand binding for MasR [163]. Thus, biological responses mediated by MasR stimulation result from MasR trafficking as well as from interaction with other receptors.

The existence of RAS alterations in patients with neurodegenerative and neuropsychiatric diseases such as AD, PD and schizophrenia (SCZ) has been proved. Studies in humans showed that Ang-(1-7) plasma levels from AD patients were lowered in relation to cognitive function compared with matched controls [143]. Accordingly, a recent study showed that ACE activity was elevated in cerebrospinal fluid (CSF) of AD patients [144]. PD patients exhibited lower plasma levels of Ang-(1-7) compared to controls, in association with increased severity of depressive symptoms [164]. ACE activity was also increased in PD patients [165]. In fact, ACE gene may be associated to genetic susceptibility to PD, mainly in older individuals [166]. In patients with SCZ, an association between increased ACE activity in plasma and cognitive deficits was also suggested [167].

Clinical evidence shows that the blockade of the pressor arm of the RAS with an ACE inhibitor (ACEi) or an Ang receptor blocker (ARB) is associated with improvement in cognitive impairment. Elderly patients treated with centrally active ACEi such as captopril exhibited a reduced rate of cognitive decline [168]. ARBs such as losartan and valsartan also improved cognitive dysfunction and dementia [169]. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a randomized, double-blind and placebo-controlled clinical trial which showed that treatment with the ACEi perindopril reduced the risk of post-stroke dementia [170]. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril reduced the cognitive decline associated with stroke [171]. In the Antihypertensives and Vascular, Endothelial, and Cognitive Function (AVEC) study, the ARB candesartan was shown to be superior to hydroclorotiazide and lisinopril in preserving the executive function [172]. ARBs reduced the incidence and progression of AD and dementia when compared to ACEIs in patients with cardiovascular disease older than 65 years [173]. Altogether this clinical evidence demonstrates that blockade of the pressor arm of the RAS, regardless of the drug class, have benefits on reducing the cognitive impairment associated to stroke and dementia.

Neuroprotective effects of ARBs and ACEi reported in animal models of PD have not yet been translated into clinical trials. A large cohort study showed that ACEi users had a lower risk of PD, suggesting a potential reduction of PD risk associated to these antihypertensive agents [174]. Treatment with telmisartan significantly decreased SCZ symptoms together with plasma levels of the pro-inflammatory marker IL-6, showing promising results regarding RAS modulation in SCZ treatment [175]. Further clinical studies in PD and SCZ are warranted to prove a net benefit regarding RAS blockade in these patients.

Besides being a central regulator of blood pressure and hydrosaline homeostasis, brain RAS also participates in the development of the nervous system and cognitive processes, including cognition, memory and learning. Stimulation of ACE2/Ang (1-7)/MasR axis at central level has been linked to neuroprotective effects, modulation of cognition, induction of angiogenesis and cerebral vasodilation. All these actions oppose to the harmful effects of the Ang II/AT1R axis. The existence of alterations in the brain Ang-(1-7)/MasR axis has been involved in the pathophysiology of neurogenic hypertension and in the development of neurological disorders such as AD, stroke, anxiety, depression and emotional stress. In this context, the depressor axis of the RAS could be thought as a potential target in the treatment of cardiovascular and neurological disorders. Central ACE2 activation and other strategies directed to increase central Ang-(1-7) levels may be considered as possible tools to treat neurodegenerative diseases in the brain. Future studies are needed to fully understand the role of central ACE2/Ang-(1-7)/MasR axis in neuroprotection.