Sex Difference in Vascular Injury and the Vasoprotective Effect of Valsartan Are Related to Differential AT 2 Receptor Expression

The angiotensin II type 2 (AT2) receptor is upregulated in pathological conditions such as vascular injury and exerts antagonistic effects against AT1 receptor-mediated actions. We examined the possibility that the sex difference in vascular remodeling is associated with altered AT2 receptor expression, which is located on the X chromosome. In this study, we examined this possibility by using AT2 receptor-null (Agtr2-) mice. Vascular injury was induced by polyethylene cuff placement around the femoral artery of wild-type (Agtr2+) and Agtr2- mice. In Agtr2+ mice, AT2 receptor expression in the injured artery was enhanced, and this increase was greater in female than in male mice, with no significant difference in AT1 receptor expression between male and female mice. Increases in neointimal formation, DNA synthesis, expression of monocyte chemoattractant protein-1, production of superoxide anion, and NADPH oxidase activity in the injured artery were attenuated in female compared with male mice. These parameters were augmented in Agtr2- mice, whereas the sex differences in these parameters were smaller in Agtr2- than in Agtr2+ mice. Treatment with a nonhypotensive dose of the AT1 receptor blocker valsartan decreased these parameters significantly in Agtr2+ mice, and these inhibitory effects of valsartan were greater in female mice. This sex difference in valsartan's inhibitory effect was less marked in Agtr2- mice. Our results suggest that the sex difference in response to vascular injury could be at least partially attributed to the exaggerated AT2 receptor expression in the injured vessel in female mice.