Background and Purpose—Protective effects of bone marrow stromal cells (MSCs) on ischemic brain damage have been highlighted. We examined the possibility that deletion of AT₂ receptor could attenuate the cerebroprotective effects of MSC using AT₂ receptor-deficient mice (Agtr2^-) and the effect of selective AT₁ receptor blocker.

Methods—Wild-type mice (Agtr2⁺) were subjected to 3 hours of focal brain ischemia followed by reperfusion (ischemia–reperfusion injury). Simultaneously, Agtr2⁺-MSC, Agtr2^--MSC, or saline was injected through the tail vein.

Results—Survival rates at 6 days after ischemia–reperfusion injury were as follows: approximately 50% in saline-injected mice, 80% in Agtr2⁺-MSC-injected mice, and 20% in Agtr2^--MSC-injected mice. Neurological deficit after ischemia–reperfusion injury was improved in Agtr2⁺-MSC-injected mice, but not in Agtr2^--MSC-injected mice. After 48 hours of ischemia–reperfusion injury, brain infarct size was reduced in Agtr2⁺-MSC-injected mice, but not in Agtr2^--MSC-injected mice. Moreover, brain edema was significantly ameliorated in Agtr2⁺-MSC-treated mice but not in Agtr2^--MSC-treated mice. Furthermore, the increase in mRNA expression of tumor necrosis factor- and monocyte chemoattractant protein-1 in the ischemic brain was less in Agtr2⁺-MSC-treated mice in the ipsilateral site, but was similar in the contralateral hemisphere. Tumor necrosis factor- level was increased in both the contralateral hemisphere and ipsilateral hemisphere of Agtr2^--MSC-treated mice. In contrast, monocyte chemoattractant protein-1 levels tended to increase Agtr2^--MSC-treated mice without a significant difference. Treatment of MSC with an AT₁ receptor blocker, valsartan, significantly improved survival rates in Agtr2^--MSC-injected mice.

Conclusions—These results suggest that AT₂ receptor signaling in MSC attenuated brain damage and neurological deficit (deleted).