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

相对于大脑的大小，大脑是体内最依赖氧气的器官，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，研究低氧应激或高海拔条件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。已有文献表明，脑血流量增加，特别是在脑干区域，反应严重的低氧刺激，通过血管扩张。尽管暴露在常压和低压(如高海拔)低氧环境下的脑血流量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差，特别是在人类中。尽管存在低氧的生理压力，但一些人在高海拔地区存活了数千年，这表明他们已经适应了低氧条件。人类对高原低氧的适应有三种成功的模式：安第斯模式(“经典适应性”红细胞增多症伴动脉低氧血症)；藏族(正常的血红蛋白浓度伴动脉低氧血症)；以及最近发现的埃塞俄比亚模式(正常的血红蛋白浓度只会导致适度的动脉低氧血症)。人类在这些人群中的脑血流调节机制还没有被比较-它们的描述将澄清我们目前对健康中脑血流调节的模糊理解，并为最大限度地提高疾病中的脑氧合提供潜在的靶点。通过结合先进的金标准脑测量技术，以及有和没有药物干预，这项研究计划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，分为两个实用主题，解决以下总体目标：1)量化缺氧可以改变海平面和高原脑血流的机制；2)探索在安第斯山脉、西藏和埃塞俄比亚人群中，人类对高原缺氧的慢性适应成功模式是否改变了调节脑血流的控制机制。这些目标将在海平面和高海拔的不同实验干预措施中得到解决。表征氧气、脑血流和脑代谢之间的这些关系，以及它们对大脑稳态的各自重要性，是提高我们对大脑生理学和其他身体系统的理解的根本步骤。揭示低氧适应的生理学基础将有助于理解与低氧耐受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.