Nitric Oxide and the Microcirculation in the Tibet Autonomous Region

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The goal of the study is to discover the mechanisms underlying the distinctive pattern of adaption to high altitude that couples very high systemic blood flow with extraordinarily high levels of nitric oxide. It is designed to discover 1) the proportional contributions to systemic flow of red blood cell velocity and capillary architecture in the microcirculation, 2) the extent to which those features of the microcirculation, where oxygen is offloaded from the blood, influence global oxygen delivery, 3) the contribution of vasodilators and angiogenic factors to red cell velocity, capillary morphology, and oxygen delivery and 4) the association of morphological and molecular markers with single-nucleotide polymorphisms in candidate genes. The goal will be achieved with simultaneous measurements at the circulatory, microcirculatory, molecular, and genetic levels using a one-shot case study design to analyze the consequences of the exceptionally large range of variation in circulating nitric oxide metabolites in the Tibetan population of Benam County, Xigatse Prefecture, Tibet Autonomous Region. This population, which includes Sherpas, is famous for its ability to live and work at altitudes where people from the elsewhere are severely impaired owing to less than sea-level amounts of oxygen in the air. The question of whether the responses are likely to be evolutionary responses honed by natural selection over more than 20,000 years or acclimatizations reached after a few years will be addressed by comparison with a sample of high-altitude Han Chinese migrants who migrated as adults. The biological basis of the ability to live at high altitudes is an important long-standing question and may offer clues to various ways people adapt to extreme environments. For examples, are certain forms of human genes more effective than others, is a lifetime of exposure a requirement, or is a certain exposure time required for anyone to establish a different physiological homeostasis. Filling the gap in our knowledge of oxygen delivery at the actual site of gas exchange in the microcirculation is important for discovering how Tibetans have normal oxygen consumption despite profound arterial hypoxia and for integrating scientific discoveries across the population, individual, organ system, molecular and genetic levels. Understanding the distinctive Tibetan pattern of adaptation to high-altitude hypoxia will help answer central questions: how do adaptations evolve, how fast do they occur, what are the genetic and adaptive origins of human biological variation, and what can be used to assist humans who lack this adaptation during times of hypoxia? The broader impact of the proposed research includes expanded multidisciplinary partnerships with Chinese and Tibetan scientists, research assistants and volunteers and students at all research phases from design through publication. Addressing the range of variation in successful responses to hypoxia in health and disease benefits society since the response can be a matter of life and death if hypoxia occurs. At present there is little understanding of why some people respond successfully to hypoxia and others do not.