Mechanisms and quantification of human cerebral blood flow regulation in acute and chronic hypoxia

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Relative to its size, the brain is the most oxygen-dependent organ in the body, but many pathophysiological and environmental processes may either cause or result in an interruption to its oxygen supply. As such, studying the brain under hypoxia stress or at high altitude is an appropriate model to investigate both acute and chronic effects of hypoxemia on cerebrovascular function. It has been well documented that cerebral blood flow increases, especially in the brainstem region, in response to the severity of hypoxic stimuli in humans via vasodilation. Although the increases in cerebral blood flow upon exposure to normo- and hypobaric (e.g., high altitude) hypoxia seems to be adequate to maintain cerebral oxygen delivery, the current understanding of these underlying mechanisms is poor, especially in humans. Despite the physiological stress of hypoxia, several human populations have survived for millennia at high altitudes, suggesting they have adapted to hypoxic conditions. There are three successful patterns of human adaptation to high-altitude hypoxia: Andean ("classic adaptation" erythrocytosis with arterial hypoxemia); Tibetan (normal hemoglobin concentration with arterial hypoxemia); and the recently identified Ethiopian pattern (normal hemoglobin concentration will only modest levels of arterial hypoxemia). The mechanisms of human cerebral blood flow regulation across each of these populations have not been compared - their description would clarify current ambiguities in our understanding of cerebral blood flow regulation in health and provide potential targets for maximizing cerebral oxygenation in disease. By combining sophisticated gold-standard brain measurement techniques, with and without pharmacological interventions, this goal of this program of research is split into two practical themes based on the divergent human responses to acute (theme one) and chronic (theme two) hypoxia that address the following general goals: 1) to quantify the mechanisms by which hypoxia can alter cerebral blood flow at both sea level and high altitude; and 2) explore if the control mechanisms that regulate cerebral blood flow are altered in chronic successful patterns of human adaptation to high-altitude hypoxia in Andean, Tibetan and Ethiopian populations. These goals will be addressed in >8 different experimental interventions at both sea level and high altitude. Characterization of these relationships between oxygen, cerebral blood flow and cerebral metabolism, and their respective importance on brain homeostasis is a fundamental step toward raising our understanding of brain physiology to that of other body systems. Uncovering the physiological basis of hypoxic adaptation will both inform understanding of hematological and other adaptations involved in hypoxia tolerance and form the basis of novel methods of treating conditions of pathological brain hypoxia.