We tested the hypothesis that small changes in ACE (angiotensin converting enzyme) expression can alter the vascular response to injury. Male mice containing 1, 2, 3 and 4 copies of the Ace gene with no detectable vascular abnormality or changes in blood pressure were submitted to cuff-induced femoral artery injury. Femoral thickening was higher in 3- and 4-copy mice (42.4±4.3, 45.7±6.5%, respectively) compared to 1- and 2-copy mice (8.3±1.3, 8.5±0.9%, respectively). Femoral ACE levels from control and injured vessels were assessed in 1- and 3- copy Ace mice, which represent the extremes of the observed response. ACE vascular activity was higher in 3- vs. 1-copy Ace mice (2.4 fold, p<0.05) in the control uninjured vessel. Upon injury, ACE activity significantly increased in both groups (2.41 fold and 2.14 fold, p<0.05, for 1- and 3-copy groups, respectively) but reached higher levels in 3 vs. 1-copy Ace mice (p<0.05). Then, pharmacologic interventions were used as a counter proof and to assess the role of angiotensin II (Ang II) on this response. Interestingly, ACE inhibition (Enalapril) and Ang II AT1 receptor blocker (Losartan) reduced intimal thickening in 3-copy mice to 1-copy mice values (p<0.05) while Ang II treatment significantly increased intimal thickening in 1-copy mice to 3-copy mice levels (p<0.05). Taken together, these data indicate that small physiologically relevant changes in ACE, not associated with basal vascular abnormalities or blood pressure levels, do influence the magnitude of cuff-induced neointimal thickening in mice.