Sex-different effect of angiotensin II type 2 receptor on ischemic brain injury and cognitive function

We previously reported that angiotensin II type 2 (AT2) receptor signaling prevents neural damage and cognitive impairment after focal cerebral ischemia. We investigated the possible roles of the AT2 receptor in the sex difference, focusing on cognitive function and ischemic brain damage using AT2 receptor-deficient mice (Agtr2−). In Agtr2−, spatial memory evaluated by the Morris water maze test was impaired in female compared with that in male Agtr2− and female wild-type (Agtr2+), while no significant sex-different change was observed in Agtr2+. Interestingly, bromodeoxyuridine incorporation assay showed a significant decrease of hippocampal neurogenesis in female Agtr2− compared with that in female Agtr2+. In contrast, ischemic area after middle cerebral artery (MCA) occlusion was significantly increased in male compared with female mice in Agtr2−, while no significant sex-different change was observed in Agtr2+. Male Agtr2− mice showed higher AT1 receptor expression and significantly impaired cerebral blood flow (CBF) in the ipsilateral side 24 hours after MCA occlusion compared with female Agtr2− mice. In conclusion, deletion of the AT2 receptor showed a sex-different effect such as a severe cognitive impairment with a decrease of hippocampal neurogenesis in females and a larger ischemic brain damage with a decrease of CBF in males.