Objectives: Crosstalk between the angiotensin (Ang)-converting enzyme (ACE)/Ang II/ Ang II type 1 (AT1) receptor axis and ACE2/Ang (1-7)/Mas axis plays a role in the pathogenesis of cardiovascular remodeling. Moreover, possible stimulation of Ang II type 2 (AT2) receptor by Ang-(1-7) has been highlighted as new axis; however, pathophysiological significance of this possibility has to be elucidated in more detail. Therefore, we examined the possibility whether ACE2/Ang (1-7)/Mas axis and Ang (1-7)/AT2 receptor axis is involved the inhibitory effects of AT1 receptor blocker (ARB) on vascular remodeling.
Methods: Ten-week-old male C57BL/6J (wild type: WT), Mas knockout (MasKO), and AT2 receptor knockout (AT2KO) mice were used in this study. Vascular injury was induced by polyethylene-cuff placement around the mouse femoral artery. After cuff placement, some mice were treated with azilsartan (0.3 mg/kg/day), an ARB, or Ang (1-7) (0.5 mg/kg per day). Two weeks after operation, femoral arteries were removed, fixed and stained by Elastica van Gieson staining for evaluating neointimal formation.
Results: Neointima formation induced by cuff placement was further increased in MasKO mice compared with WT mice. Treatment with azilsartan or Ang-(1-7) decreased neointima area and vascular smooth muscle cell proliferation, and attenuated the increases in the mRNA level of MCP-1, TNF-α and IL-1β in the injured artery in WT mice without influencing blood pressure. These inhibitory effects of azilsartan or Ang-(1-7) were less in Mas KO mice. One week after cuff placement, the mRNAs of ACE2 and Mas in the injured artery were markedly decreased in WT mice. Administration of azilsartan or Ang-(1-7) attenuated the decrease in ACE2 mRNA, but not affect the decrease in Mas mRNA. Neointima formation in AT2KO mice was more exaggerated compared with that in WT mice. Interestingly, we observed that inhibitory effect of Ang-(1-7) on neointima formation was less in AT2KO mice compared with WT mice.
Conclusion: These results suggest that blockade of AT1 receptor by azilsartan could enhance the activities of the ACE2/Ang (1-7)/Mas axis and ACE2/Ang-(1-7)/AT2 receptor axis, thereby inhibiting the neointima formation.