MECHANISMS OF HUMAN CEREBRAL BLOOD FLOW REGULATION IN ACUTE AND LIFELONG HYPOXIA IN LOWLANDERS AND INDIGENOUS POPULATIONS

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BACKGROUND: 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 a compromise to its oxygen supply. As such, studying the brain under acute and/or repetitive 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 in response to the severity of hypoxic stimuli in humans via vasodilation. Although the increases in cerebral blood flow (CBF) upon exposure to acute and normo- and hypobaric (e.g., high altitude) hypoxia seem 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 Indigenous 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, Tibetan and Ethiopian pattern. Acute and prolonged ascent or residency at high altitude, thus represents a complex stimulus to the brain, the nature of which is not well understood, particularly in light of sustained alterations and compensations in arterial acid-base balance and metabolism. By combining sophisticated gold-standard brain measurement techniques, this goal of this program of research is split into two practical themes based on the divergent human responses to acute and prolonged (theme one) and lifelong (theme two) hypoxia that address the following specific questions: QUESTION 1: What are the main mechanism(s) by which acute hypoxia induces cerebral vasodilation and maintenance of cerebral oxygen delivery? QUESTION 2:What are the main mechanism(s) by which prolonged hypoxia induces cerebral vasodilation and maintenance of cerebral oxygen delivery?. QUESTION 3: Has CBF regulation differentially evolved amongst the different phenotypes of adaptation to high altitude? SIGNIFICANCE: Addressing the novel questions outlined in this proposal will enrich our understanding of the fundamental mechanisms governing CBF in conditions of acute and/or, and lifelong hypoxia. Continuing fieldwork in Indigenous high altitude and diving populations is urgent since modernization and migration are changing the traditional ways of life and patterns of exposure to the environment among highlanders everywhere. Uncovering the physiological basis of hypoxic adaptation will inform understanding of hematological and other adaptations involved in hypoxia tolerance and will moreover facilitate explication of the processes by which humans have evolved to their environments.