Adaptation to continued moderate hypoxia in the rat brain includes structural and metabolic changes. The most striking evidence of this hypoxia induced metabolic and vascular plasticity is capillary angiogenesis characterized by increased capillary density. This project proposes to study the time course of angiogenesis in response to continued and intermittent hypoxia, and return to normoxia. The appearance and disappearance of capillaries will be documented in the standard adult Wistar rat model and compared to the response of obese/hypertensive, lean/hypertensive, and streptozotocin-induced chronic hyperglycemic rats. Functional consequences of vascular re-structuring will be examined through measurements of blood flow and mean transit time and blood volume under resting conditions and in response to challenges of acute hypoxia, acute hypercapnia and acetazolamide. Brain energy metabolites and intracellular Ph will be measured to characterize the metabolic adaptations in these models. Dynamic metabolic responses to hypoxia in adapted and non-adapted rats will be studied by H and 31P-NMR spectroscopy. These studies will help to define the boundaries of the structural and metabolic changes that occur in response to continued hypoxic exposures. Neuronal function is coupled tightly to both blood flow and oxygen metabolism. This tight coupling directly suggests mechanisms which could explain the cognitive impairments commonly associated in humans with sleep-disordered breathing. Certainly, acute moderate hypoxemia might impair neuronal function. Incomplete or unsuccessful adaptation to continued hypoxia could also explain functional impairment. Finally, even successful adaptation to continued hypoxemia might result in cognitive impairment because of the functional consequences of the structural adaptations. These considerations provide a rationale for obtaining evidence of similar metabolic and vascular plasticity in human subjects that have continuous hypoxemic episodes. The extent of metabolic and vascular adaptation to chronic hypoxia will be tested in human patients using positron emission tomography for measuring blood flow, blood volume, oxygen extraction fraction and glucose consumption in sleep apneic patients. Additional protocols for studying patients using 1H and 31P spectroscopy will be pursued based on the animal spectroscopy studies. It is our long-term goal to provide a basic understanding of the physiological and pathophysiological responses triggered by hypoxic exposure. This information would be used to diagnose and quantify hypoxic exposure in human subjects using currently available PET and MRI- MRS methods; and would also provide tools for determining and need for, and evaluating the success of therapeutic interventions.
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