Neurons, glia and blood vessels form a highly integrated functional unit collectively termed """"""""the neurovascular unit"""""""" that couples blood flow and metabolism and coordinates cross-talk between cell and tissue elements during health and disease. We provide preliminary evidence for a novel form of neurovascular coupling in which (1) intense neuroglial depolarization is accompanied by abrupt vasoconstriction during focal cerebral ischemia, and (2) by which anoxic depolarization (AD) and peri-infarct spreading depolarizations (PIDs) cause step-wise reductions in blood flow, and by so doing, expand the hypoperfused territory at risk. To obtain preliminary data, we performed two-dimensional cerebral blood flow (CBF), volume and oxygenation mapping with high temporal and spatial resolution (real-time laser speckle flowmetry, simultaneously with multiwavelength reflectance imaging of oxyhemoglobin, deoxyhemoglobin, and total hemoglobin). Here we build on these findings and expand on this novel mechanism to explore the vascular consequences of neuroglial depolarization during ischemia. Our overall hypothesis is that AD and PIDs cause abrupt decreases in cortical perfusion, and by so doing, adversely affect the neurovascular unit within depolarized ischemic tissue, a novel concept of infarct evolution. We postulate that by attenuating AD and PIDs, the occurrence of these punctuated vasoconstrictor events can be inhibited, and the expanding CBF deficit prevented. We propose three specific aims:
Aim 1 will test the novel hypothesis that punctuated depolarizing events early after ischemia (i.e., AD and PIDs) cause acute severe vasoconstriction, and by so doing, further compromise CBF.
Aim 2 will test the hypothesis that treatments known to preserve membrane ionic gradients (e.g., inhibit K+ efflux), such as inhibitors of cortical spreading depression (CSD) (e.g., topiramate, gap junction blockers, sigma-1 agonists), attenuate vasoconstriction, and halt the worsening of CBF during acute stroke as a fundamental mechanism of tissue protection.
Aim 3 will test the hypothesis that impaired vasodilator mechanisms exacerbate the abrupt vasoconstriction during ischemic neuroglial depolarization via molecular changes in vasomotor regulatory proteins such as endothelial nitric oxide synthase. By so doing, we hope to better understand vascular and hemodynamic mechanisms underlying infarct expansion during acute stroke and to develop more rational approaches to protect ischemic tissue.
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