Mechanisms of Diabetes-Mediated Cerebrovascular Injury in Ischemic Stroke

Augusta University, Augusta GA

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Abstract

Type 2 diabetes is an important risk factor for cerebrovascular disease and is a reliable predictor of increased morbidity and mortality following an acute ischemic stroke (AIS). Our lab has demonstrated that when compared to Wistar (control) rats, 3 h middle cerebral artery occlusion (MCAO) followed by 21 h reperfusion induces greater vascular injury (i.e., increased hemorrhage and edema) in diabetic Goto-Kakizaki (GK) rats, despite reduced infarct volume. In addition, the ensuing neurobehavioral deficits are more severe in diabetic rats. Singly, diabetes alters vessel morphology and function;however, the combined effect of diabetes and focal ischemia on cerebrovascular reactivity/integrity, stroke pathophysiology, and neurobehavioral outcome is unclear. The objective of this study is to test the central hypothesis that diabetic conditions augment excess generation of peroxynitrite upon ischemia/reperfusion (I/R) injury which leads to alterations in the vascular actin cytoskeleton and the promotion of matrix metalloproteinase (MMP)-mediated disruption of the blood brain barrier, thereby contributing to increased edema, hemorrhage, and a corresponding reduction in infarct volume. We will test this hypothesis in two specific aims using diabetic GK rats and Wistar (control) rats. In Aim 1, we will determine how peroxynitrite regulates cytoskeletal-myogenic interactions in the cerebrovasculature following I/R injury as potential vascular mechanisms of increased hemorrhagic transformation (HT) and edema. In Aim 2, we will determine the separate effects of glucose control, peroxynitrite blockade, and acute NFkB inhibition as potential mechanisms to prevent increased MMP activity and the development of HT in diabetes. Also, we will determine the effect of acute MMP inhibition by minocycline on HT and edema formation after transient MCAO. Presently, there is only one effective treatment for stroke. By studying the effects of these therapeutic agents in diabetic models, we hope to uncover novel insight into the mechanisms of diabetes-mediated vascular injury after AIS and advance the field of stroke prevention and treatment.