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To investigate the role of brain angiotensin II (ANG II) in the pathogenesis of injury following ischemic stroke, mice overexpressing renin and angiotensinogen (R + A +) and their wild-type control animals (R - A -) were used for experimental ischemia studies. Focal brain ischemia was induced by middle cerebral artery occlusion (MCAO). The severity of ischemic injury was determined by measuring neurological deficits and histological damage at 24 and 48 h after MCAO, respectively. To exclude the influence of blood pressure and local collateral blood flow, brain slices were used for oxygen and glucose deprivation (OGD) studies. The severity of OGD-induced damage was determined by measuring indicators of tissue swelling and cell death, the intensity of the intrinsic optical signal (IOS), and the number of propidium iodide (PI) staining cells, respectively. Results showed 1) R + A + mice showed higher neurological deficit score (3.8 [+ or -] 0.5 and 2.5 [+ or -] 0.3 for R + A + and R - A -, respectively, P < 0.01) and larger infarct volume (22.2 [+ or -] 1.6% and 14.1 [+ or -] 1.2% for R + A + and R - A -, respectively, P < 0.01); 2) The R + A + brain slices showed more severe tissue swelling and cell death in the cortex (IOS: 140 [+ or -] 6% and 114 [+ or -] 10%; PI: 139 [+ or -] 20 cells/field and 39 [+ or -] 9 cells/field for R + A + and R - A -, respectively, P < 0.01); 3) treatment with losartan (20 [micro]mol/1) abolished OGD-induced exaggeration of cell injury seen in R + A + mice. The data indicate that activation of ANG II/[AT.sub.1] signaling is harmful to brain exposed to ischemia. [AT.sub.1] receptor; mouse; losartan; middle cerebral artery doi: 10.1152/ajpregu.91040.2008.

For determining the implications of circulating endothelial progenitor cells (cEPCs) and cellular membrane microparticles (MPs) in diabetic stroke, levels of EPCs, EPC-MPs, and endothelium-derived MPs (EMPs) and their correlations with blood glucose concentration, cerebral microvascular density (cMVD), and ischemic damage were investigated in type 2 diabetic db/db and db/+ (wild-type control) mice. Therapeutic efficacy of EPC infusion (preincubated with MPs) was also explored. Ischemic stroke was induced by middle cerebral artery occlusion (MCAO) surgery. Ischemic damage and cMVD were determined using histological analyses. The levels of cEPCs and MPs were determined using flow cytometric analyses. EPC generation and functions were evaluated by in vitro cell cultures. Results showed the following. 1) In db/db mice, the basal level of cEPCs was less and cMVDs were lower, but the levels of circulating EPC-MPs and EMPs were more; 2) MCAO induced a larger infarct volume and less of an increase in cEPCs in db/db mice; 3) the level of cEPCs correlated with blood glucose concentration (negatively), cMVD (positively), and ischemic damage (negatively), but the levels of EPC-MPs and EMPs correlated inversely with those parameters; 4) EPCs were reduced and dysfunctional in db/db mice, and preincubation with db/db MPs impaired EPC functions; and 5) infusion of EPCs preincubated with db/+ MPs increased the level of cEPCs and reduced ischemic damage, and these beneficial effects were reduced or lost in EPCs preincubated with db/db MPs. These data suggest that reduced cEPCs, impaired EPC generation/function, and increased production of MPs might be the mechanisms responsible for increased ischemic damage seen in db/db mice.