Because decreased ACE2 in the central nervous system is associated with multiple cardiovascular diseases, compensation by ACE2, as a result of increasing or activating this enzyme, in the brain could provide beneficial effects on these diseases. Several studies showed the effects of ACE2 on prevention or attenuation of hypertension. Using adenovirus coding for ACE2, Sriramula et al. [36] showed that PVN-targeted ACE2 overexpression attenuates the Ang II-induced pressor response in rats. Using a new transgenic mouse model (syn-hACE2) with neuron-targeted ACE2 overexpression, we found that the development of Ang IIinduced neurogenic hypertension was blunted [33••]. In additional experiments, the syn-hACE2 mice were bred with chronically hypertensive transgenic mice expressing both human renin and AGT genes [37] , to generate a tripletransgenic model (SARA) with elevated Ang II throughout the body and overexpression of human ACE2 selectively in the brain. Following chronic measurement of blood pressure in SARA mice, we observed that central overexpression of ACE2 significantly decreases baseline blood pressure in these chronically hypertensive mice [31••]. However, the blood pressure was not normalized due to the chronic and widespread expression of Ang II in the periphery. Nevertheless, our observations are consistent with previous reports from Yamazato et al. [28] and our group [30] showing the antihypertensive effects of ACE2 in specific brain nuclei, such as RVLM and subfornical organ. In addition to these gene transfer approaches, Cangussu et al. [38] showed that increases in ACE2 and Mas mRNA IML-intermediolateral cell column; NA-nucleus ambiguus expression in the hypothalamus following exercise training in 2K1C rats are associated with a reduction of the increased systolic arterial pressure in these animals, although ACE2 levels were not altered in these hypertensive rats before exercise training compared with sham controls. Besides the role of ACE2 in the regulation of blood pressure, Lima et al. [39] showed that central activation of ACE2 by intracerebroventricular injection of XNT, an activator of endogenous ACE2, attenuates air jet stress-induced tachycardia in rats, suggesting the beneficial effects of ACE2 on cardiac function.