Crackower et al. [64] were the first to test ACE2 as the gene underlying the blood pressure locus on the X chromosome. They showed reduced expression of renal ACE2 in the salt-sensitive Sabra hypertensive rat compared with the normotensive rat. Both spontaneously hypertensive rats (SHR) and spontaneously hypertensive stroke-prone rats (SHRSP) rats showed reduced renal ACE2 protein levels compared with the normotensive Sabra and Wistar Kyoto (WKY) strains. Two other groups confirmed some of these findings showing lower renal ACE2 mRNA, protein, and activity in the SHR compared to WKY rats [65, 66] . However, other investigators were unable to detect any difference in renal ACE2 mRNA, protein, and activity between adult hypertensive rats and their normotensive controls [67] . Rentzsch et al. [68] , assessed in SHRSP (that display reduced ACE2 mRNA and protein expression compared with control animals in the kidney) the role of ACE2 in the pathogenesis of hypertension. They generated transgenic rats on a SHRSP genetic background expressing the human ACE2 in vascular smooth muscle cells by the use of the SM22 promoter, called SHRSP-ACE2. In these transgenic rats, vascular smooth muscle cells (VSMC) expression of human ACE2 was confirmed by RNase protection, real-time RT-PCR, and ACE2 activity assays. Transgene ACE2 expression leads to significantly increased circulating levels of Ang- (1-7) , a prominent product of ACE2. Mean arterial blood pressure was reduced in SHRSP-ACE2 compared to SHRSP rats, and the vasoconstrictive response to intraarterial administration of Ang II was attenuated. The latter effect was abolished by previous administration of an ACE2 inhibitor. To evaluate the endothelial function in vivo, endotheliumdependent and endothelium-independent agents such as acetylcholine and sodium nitroprusside, respectively, were applied to the descending thoracic aorta and blood pressure was monitored. Endothelial function turned out to be significantly improved in SHRSP-ACE2 rats compared to SHRSP. These data indicate that vascular ACE2 overexpression in SHRSP reduces hypertension probably by local Ang II degradation and by improving endothelial function [68] .