Abstract 875: Deletion of AT2 Receptor Attenuates Protective Effects of Bone Marrow Stromal Cells on Ischemic Brain Damage
Introduction: Protective effects of bone marrow stromal cells (BMSC) on ischemic brain damage have been highlighted. Angiotensin (Ang) II could be involved in bone marrow cell-differentiation; however, roles of Ang II receptors in BMSC on stroke are not well known. We recently reported the significance of AT2 receptor activation in protection of neural damage via upregulation of MMS2, a neuroprotective factor.
Hypothesis: We examined the possibilities that blocking of AT2 receptor stimulation would attenuate the cerebroprotective effects of BMSC, using two different experimental mouse models.
Wild-type (C57B6, 10 weeks of age) mice (Wt) underwent 3 hours of focal cerebral brain ischemia by middle cerebral artery occlusion (MCAO), followed by reperfusion. Simultaneously, Wt-BMSC (n=15), Wt-BMSC treated with Ang II (10−7 M) (n=11), BMSC prepared from AT2 receptor-deficient mice (AT2KO) (n=10), or PBS (n=15) was injected into the mice from tail vein.
Chimeric mice were generated by transplantation of bulk marrow cells (1x106) isolated from Wt (Wt→Wt, n=10) or AT2KO (AT2KO→Wt, n=10) after 9Gy radiation.
Mice were subjected to ischemia-reperfusion. 6 weeks after transplantation. Expressions of mRNAs were measured by real time RT-PCR. Ischemic area was assessed by triphenyltetrasodium chloride staining.
Results: Survival rates 1 week after MCAO are as follows; approximately 40% in PBS injected mice, 80% in BMSC injected mice, 30% Ang II-treated BSMC injected mice, and 20% in BMSC from AT2KO injected mice. Neurological deficit after MCAO was improved in BMSC injected mice, but no significant changes were observed in AT2KO- or Ang II-treated BMSC injected mice. MCP-1 mRNA expression was less in BMSC treated mice. In chimeric mice, ischemic volume of AT2KOWt 24 hours after operation was larger than Wt→Wt. Neurological deficit in AT2KO→Wt was more severe than in Wt→Wt. MMS2 mRNA expression in ipsilateral hemisphere was increased.
Conclusions: These results suggested that AT2 receptor signaling in BMSC attenuated brain damage, partly due to decrease in inflammation and increase in MMS2 expression, and that ARB could exert cerebroprotective effects at least partly due to stimulation of AT2 receptor in bone marrow derived cells.