Hemorrhagic transformation upon reperfusion
therapy has focused attention on
ischemia-induced endothelial dysfunction. This study examined whether
hyperglycemia may induce hemorrhagic transformation by enhancing endothelial mitochondrial damage during
ischemia and whether preconditioning (PC) stimuli may limit
ischemia-induced endothelial damage. In vivo, rats received 2.8 M
D-glucose or
arabinose (1 ml/100 g; i.p.) prior to undergoing two hours of
middle cerebral artery occlusion and transcardiac fixation for electron microscopy. In vitro, brain endothelial cells were exposed to a PC impulse (short-term
oxygen glucose deprivation; OGD) prior to an injurious event (5 hours OGD). Endothelial injury was assessed by measuring
lactate dehydrogenase release.
Hyperglycemia during
cerebral ischemia resulted in marked changes in endothelial morphology and mitochondrial swelling. Thus, in the ischemic hemisphere, there was no evidence of endothelial mitochondrial swelling in normoglycemic rats (mean profile width 0.22 +/- 0.04 vs. 0.17 +/- 0.01 microm in contralateral hemisphere) but there was marked swelling in hyperglycemic rats (0.44 +/- 0.02 microm). In vitro, cells preconditioned with one hour of OGD one day prior to 5 hours of OGD, showed reduced
lactate dehydrogenase release (p < 0.05). In conclusion,
hyperglycemia may have specific adverse effects on endothelial cell mitochondria during
ischemia. Preventing those effects may help to ameliorate blood-brain barrier disruption on reperfusion. Insights into how to prevent endothelial injury may come from determining the mechanisms involved in endothelial preconditioning.