nt in cardiomyocytes from Mas-deficient mice \[[@B76]\]. Recently, Gomes et al. \[[@B77]\] found that the treatment of isolated cardiomyocytes of rats with Ang-(1--7) efficiently prevents the Ang-II-induced hypertrophy by modulating the calcineurin/NFAT signaling cascade. These effects were blocked by NO synthase inhibition and by guanylyl cyclase inhibitors, indicating that these effects are mediated by the NO/cGMP pathway.

Also, Ang-(1--7) inhibits serum-stimulated mitogen-activated protein kinase (MAPK) activation in cardiac myocytes \[[@B85]\] and prevents the Ang-II-mediated phosphorylation of ERK1/2 and Rho kinase in hearts in a dose-dependent manner \[[@B79]\]. In line with these data, activation of endogenous ACE2 significantly reduced the phosphorylation of ERK1/2 in hearts of hypertensive rats (SHRs) \[[@B48]\]. However, Mercure et al. \[[@B19]\] reported that overexpression of Ang-(1--7) in hearts of rats decreases the Ang-II-induced phosphorylation of c-Src and p38 kinase, whereas the increase in ERK1/2 phosphorylation was unaffected by the expression of the transgene, thereby suggesting a selective effect of Ang-(1--7) on intracellular signaling pathways related to cardiac remodeling.

Overall, these data reveal a key role of the ACE2/Ang-(1--7)/Mas axis in the pathophysiology of the cardiac structure and function. Activation of this axis might be an important strategy to develop a new generation of cardiovascular therapeutic agents against cardiac dysfunction and pathological remodeling of the heart.

3. Vascular ACE2/Ang-(1--7)/Mas Axis {#sec3}
====================================

Early studies have reported the endothelium as the major site for generation \[[@B67]\] and metabolism \[[@B41]\] of Ang-(1--7). In addition to Ang-(1--7), endothelial cells also express ACE2 and Mas \[[@B80], [@B81]\]. Thus, now it is recognized that the ACE2/Ang-(1--7)/Mas axis is present in vascular endothelial cells and modulates its function promoting vasorelaxation \[[@B82]\], reduction of the oxidative stress \[[