T he renin-angiotensin system (RAS) is well known for its physiological and pathophysiological roles in the regulation of blood pressure (BP) and cardiovascular function. 1,2 A new component of the RAS, angiotensin-converting enzyme (ACE) type 2 has been identified, from human heart failure ventricle and lymphoma cDNA libraries (reviewed elsewhere 3,4 ). Although the angiotensin-converting enzyme type 2 (ACE2) transcript was first described in heart, kidney and testis, additional studies reported ACE2 mRNA in rat medulla oblongata 4 and ACE2 activity in mouse brain. 5 Recently, we showed the presence of both ACE2 protein and mRNA widespread throughout the murine brain, in regions involved in the central regulation of cardiovascular function as well as noncardiovascular regions. 6 ACE2 converts Ang II into the vasodilatory peptide Ang-(1-7) with an affinity 400-fold higher than for Ang I. 7 In the central nervous system (CNS), Ang-(1-7) has been shown to enhance sensitivity of the bradycardic component of the cardiac baroreceptor reflex 8 and to promote vasodilation in hypertensive animals. 9,10 As a key enzyme in generating Ang-(1-7), ACE2 is thought to be a pivotal player in central BP regulation. 3,5 Several evidences from various laboratories have shown the beneficial effects of peripheral ACE2 in the regulation of cardiovascular hypertrophy and BP control. 10 -12 In the CNS, using a lentivirus coding for ACE2, Yamazato et al previously showed that ACE2 overexpression in the rostral ventrolateral medulla, could reverse hypertension in spontaneously hypertensive rats (SHR). 13 More recently, we reported that brain-targeted ACE2 overexpression in the subfornical organ (SFO) prevents the acute Ang II-mediated pressor and Original

The G protein-coupled receptor Mas was recently described as an angiotensin-(1-7) [ANG-(1-7)] receptor. In the present study we evaluated the anatomical localization of Mas using immunofluorescence in the central nervous system of adult male Wistar rats. An abundant labeling was found in the hippocampus, amigdala, anterodorsal thalamic nucleus, cortex, and hypoglossal nucleus. More importantly, a dense ANG-(1-7) receptor Mas immunoreactivity was observed in cardiovascular-related areas of the medulla and forebrain, shown in several previous studies as sites for the action of ANG-(1-7) in the brain. A strong staining was found in the nucleus of the solitary tract, caudal and rostral ventrolateral medulla, inferior olive, parvo and magnocellular portions of the paraventricular hypothalamic nucleus, supraoptic nucleus, and lateral preoptic area. Furthermore, Mas staining was predominantly present in neurons. At the medullary sites, a specific and high-intensity binding for rhodamine-ANG-(1-7) was also shown. The specific ANG-(1-7) binding was completely displaced by the anti-Mas antibody or by the ANG-(1-7) antagonist, A-779. The data presented provide the first anatomical basis for the physiological role of ANG-(1-7)/Mas axis in the modulation of different cardiovascular functions and give new insights for clarifying the role of ANG-(1-7) in the central nervous system.

No abstract