Mechanisms of Diabetes-Mediated Cerebrovascular Injury in Ischemic Stroke

Abstract

Diabetes increases the risk of cerebrovascular disease and is a reliable predictor of increased morbidity and mortality following acute ischemic stroke. The objective of the current study was to investigate the underlying mechanisms by which diabetes-mediated vascular dysregulation contributes to greater injury and poor stroke outcomes. We hypothesized that peroxynitrite mediates vascular dysfunction in diabetes by destabilizing the vascular smooth muscle actin cytoskeleton. In addition, we proposed that excess peroxynitrite formation and inflammation during ischemia/reperfusion injury in pre-existing diabetes amplifies the proteolytic activity of matrix metalloproteinases (MMPs), thereby contributing to greater vascular injury (i.e., edema and hemorrhagic transformation) and neurological deficit. Using a modified oxygen-glucose deprivation protocol, we examined the effects of hypoxia on cerebral macrovascular reactivity. We found that peroxynitrite mediates hypoxia-induced loss of myogenic tone and medial thickening in cerebral resistance vessels isolated from type 2 diabetic rats. Furthermore, we demonstrated that reductions in polymerized actin cytoskeletal filaments following hypoxia exposure in these vessels cannot be attributed to peroxynitrite nitration, suggesting that an alternate target or different type of peroxynitrite-mediated protein modification may be involved. Targeting mediators of stroke-induced vascular injury at reperfusion was more beneficial in diabetic animals compared to controls. Acute administration of FeTPPs, curcumin, and minocycline at reperfusion in experimental stroke successfully reduced hemorrhagic transformation in all diabetic animals. This reduction in bleeding was associated with decreased MMP-9 activity in cerebral macrovessels. Administration of curcumin and minocycline attenuated edema formation in these animals. Functional outcomes were also improved in varying degrees by these therapies. Based on the findings of these studies, we concluded that oxidative stress, inflammation, and MMP activity in the cerebrovasculature of diabetic animals play a significant role in stroke pathologies that contribute to worse outcomes. Therefore, the following dissertation research has the potential to reduce the gap in knowledge of how pre-existing diabetes contributes to stroke pathophysiology and will potentially aid in the development of novel therapeutic strategies tailored to the diabetic population.