Mitochondrial influences on cerebral arteries

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DESCRIPTION (provided by applicant): Our proposal is based upon new and important findings involving changes in mitochondrial structure and function in cerebral arteries after ischemia which are of scientific interest because they overturn accepted thinking concerning mitochondrial status and function after ischemia. These findings are of translational interest because they open up novel therapeutic avenues which can be used in people following strokes. Our overall hypothesis, derived from our discoveries, is that naturally occurring and drug inducible changes in mitochondria, primarily in endothelium following ischemia, lead to improved cerebral vascular function, preserved blood-brain barrier, and reduced neurological injury. We find that mitochondria are more resiliant after ischemic insult than previously believed and thus represent a novel therapy in stroke patients. The stroke model we use induces patterns of cerebral vascular and brain injury similar to those seen in patients in which the vascular occlusion is not removed until 3 or more hours following the onset of stroke. Several studies have shown that tPA administration in a 3- to 4.5-hour window after stroke onset shows a modest therapeutic benefit with little benefit beyond 4.5 hours. These patients in the 3-4.5 hour post-onset period represent a large and extremely vulnerable population. We expect that mitochondrial targeting in addition to clot removal will lessen morbidity and mortality in these patients. We will test our hypothesis in cultured cerebral vascular endothelial cells, isolated cerebral arteries, and the in vivo cerebral circulation. Aim 1. Determination of "naturally" occurring morphological and functional changes in mitochondria in the cerebral vasculature following ischemic stress. We will test the hypothesis that structural changes in mitochondria, including size, numbers, and/or protein content, especially in endothelium, are correlated with functional changes involving maintained dilator and protective responses following ischemia. Aim 2. Determination of "inducible" changes in mitochondrial dynamics in the cerebral vasculature following ischemic stress. We will test the hypothesis that pharmacologically-induced post-conditioning will further improve upon natural mitochondrial-dependent processes in the cerebral circulation following ischemia.