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

相对于它的大小，大脑是身体中最依赖氧气的器官，但许多病理生理和环境过程可能导致或导致其氧气供应中断。因此，研究缺氧应激或高海拔下的大脑是研究低氧血症对脑血管功能的急性和慢性影响的合适模型。有充分的证据表明，在人类缺氧刺激的严重程度下，通过血管舒张，脑血流量增加，特别是在脑干区域。虽然暴露于常压和低压（如高海拔）缺氧时脑血流量的增加似乎足以维持脑氧输送，但目前对这些潜在机制的了解很少，特别是在人类中。尽管缺氧的生理压力，一些人类种群在高海拔地区存活了几千年，这表明他们已经适应了缺氧的条件。人类适应高海拔缺氧的成功模式有三种：安第斯（“经典适应”红血病伴动脉低氧血症）；藏族（血红蛋白浓度正常伴动脉低氧血症）；以及最近发现的埃塞俄比亚模式（正常血红蛋白浓度只会导致中度动脉低氧血症）。这些人群的脑血流调节机制尚未进行比较-它们的描述将澄清目前我们对健康脑血流调节的理解中的模糊之处，并为在疾病中最大化脑氧合提供潜在的靶点。通过结合复杂的金标准脑测量技术，有或没有药物干预，该研究项目的目标根据人类对急性（主题一）和慢性（主题二）缺氧的不同反应分为两个实际主题，解决以下总体目标：1)量化缺氧可以改变海平面和高海拔脑血流量的机制；2)探索在安第斯、西藏和埃塞俄比亚人群中，调节脑血流量的控制机制是否在人类适应高海拔缺氧的慢性成功模式中发生了改变。这些目标将在b>8不同的实验干预中解决，在海平面和高海拔。表征氧、脑血流量和脑代谢之间的这些关系，以及它们各自对脑稳态的重要性，是将我们对脑生理学的理解提高到对其他身体系统的理解的基本步骤。揭示低氧适应的生理基础将有助于理解与低氧耐受性有关的血液学和其他适应，并为治疗病理性脑缺氧的新方法奠定基础。

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.