Hypoxia is one of the more common and serious stresses challenging metabolic homeostasis. Yet, both shorter and longer term adaptations allow metabolic, vascular and ventilatory adjustments to hypoxia that maintain normal brain function. The mechanisms that regulate the adaptive response are not well known or understood. It is the overall long term goal of this proposed research project to elucidate these mechanisms which fall into 2 categories. First, there are brainstem integrated control systems that adjust ventilation rates, blood pressure and cerebral blood flow to provide acute responses to hypoxic exposure. Second, persistent hypoxic exposure leads to gene-controlled reversible adaptive responses that include systemic (increased red cell volume through erythropoietin activation) and central (increased capillary density through angiogenesis and hypometabolism) components. This indicates a principle of structural and functional plasticity in the postdevelopmental, adult mammalian brain at a level not previously appreciated. This is significant because the gene mechanisms responsible for these responses appear to be activated in the pathophysiological responses to many other sources of metabolic stress such as tumors, ischemia, reperfusion injury, stroke, and aging. This application proposes to use the well-established model of inducing brain metabolic and vascular adaptation to hypobaric hypoxia in rats to focus on several questions concerning the control mechanisms of hypoxic adaptation and de-adaptation: 1) the hypothesis that unsuccessful adaptation to hypoxia as occurs for example in high altitude cerebral edema, results from vasogenic brain edema as a consequence of the early stages of a too vigorous cytokine stimulated angiogenesis, 2) the control mechanisms and signals that control the adaptive brain blood flow response to continued hypoxia, 3) the role that programmed cell death might play in the microvascular regression that accompanies de-adaptation after return to a normoxic environment. A combination of techniques will be used to measure brain metabolites (quantitative microhistochemistry), intracellular pH (imaging histophotometry), blood flow (iodoantipyrene autoradiography), ultrastructural indicators of cell division and cell death (electron microscopy), brainstem function (non-invasive plethysmography), cytokines and growth factors (such as vascular endothelial growth factor, hypoxia inducible factor, angiopoietin-1 and -2) by molecular techniques (Western and Northern blot analyses, in situ hybridization and PCR).
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