Objective: Angiotensin-(1-7) [ANG-(1-7)] has been reported to attenuate neointimal formation after vascular injury and stent implantation in rats, but the mechanism remains mostly unresolved. Interestingly, the levels of circulating transforming growth factor-beta1 (TGF-beta 1) after myocardial infarction were suppressed by ANG-(1-7), which suggests a possible downstream target for the anti-remodeling action of ANG-(1-7). Our study focused on the effects of ANG-(1-7) on vascular remodeling, including neointimal formation and collagen synthesis, and determining whether or not these effects were dependent upon the TGF-beta signaling pathway. Methods: Thirty-two New Zealand white rabbits underwent sham surgery or angioplasty in abdominal aorta. The animals were divided into four groups, which were sham, control, ANG-(1-7), and ANG-(1-7)+ A-779. Subsequently, an osmotic minipump was implanted to deliver saline, ANG-(1-7) (576 mu g kg(-1) d (-1)) or ANG-(1-7) + A-779 (576 mu g kg(-1) d(-1)) for 4 weeks. Results: The ANG-(1-7) group displayed a significant reduction in neointimal thickness (207.51 +/- 16.70 mu m vs. 448.08 +/- 15.30 mu m, P < 0.001), neointimal area (0.266 +/- 0.009 mm(2) vs. 0.408 +/- 0.002 mm(2), P < 0.001), and restenosis rate (28.13 +/- 2.74% vs. 40.13 +/-2.74%, P < 0.001) when compared to the control group. ANG-(1-7) also inhibited collagen synthesis by significantly decreasing the mRNA expression of Collagen I and Collagen III (vs. Control group: 0.2190 +/- 0.0036 vs. 0.3852 +/- 0.0212, P < 0.001 and 1.1328 +/- 0.0554 vs. 1.7378 +/- 0.1164, P < 0.001, respectively). Furthermore, the expression of TGF-beta 1 and phosphor-Smad2 (p-Smad2) were significantly suppressed by ANG-(1-7) (vs. Control group: 1.21 +/- 0.07 vs. 1.54 +/- 0.08, P < 0.001 and 0.31 +/- 0.01 vs. 0.43 +/- 0.02, P < 0.001, respectively), but no effect on p38 phosphorylation was observed. [D-Ala(7)]-ANG-(1-7) (A-779), showed a tendency to attenuate the anti-remodeling effects of ANG-(1-7). Conclusion: ANG-(1-7) decreases the amount of vascular remodeling, including a reduction in neointimal formation and collagen synthesis, after angioplasty in rabbits. The responsible mechanism may function through the possible down-regulation of TGF-beta 1 levels and inhibition of the Smad2 pathway. (C) 2009 Elsevier Inc. All rights reserved.