Arterial stiffness, frequently associated with hypertension, is associated with disorganization of the vascular wall and has been recognized as an independent predictor of all-cause mortality. The identification of the molecular mechanisms involved in aortic stiffness would be an emerging target for hypertension therapeutic intervention. This study evaluated the effects of perindopril on pulse wave velocity (PWV) and on the differentially expressed proteins in aorta of spontaneously hypertensive rats (SHR), using a proteomic approach. SHR and Wistar rats were treated with perindopril (SHR ) or water (SHRc and Wistar rats) for 8 weeks. At the end, SHR presented higher systolic blood pressure (SBP, +70%) and PWV (+31%) compared with Wistar rats. SHR had higher values of nitrite concentration and lower PWV compared with SHR . From 21 upregulated proteins in the aortic wall from SHR , most of them were involved with the actin cytoskeleton organization, like and . After perindopril treatment, there was an upregulation of the ( ), which normally inhibits the pathway and may contribute to decreased arterial stiffening. In conclusion, the results of the present study revealed that treatment with perindopril reduced SBP and PWV in SHR. In addition, the proteomic analysis in aorta suggested, for the first time, that the pathway may be inhibited by perindopril-induced upregulation of or increases in NO bioavailability in SHR. Therefore, we may propose that activation of or inhibition of pathway could be a possible strategy to treat arterial stiffness.