The overall theme of this proposal is to explore the fundamental mechanisms whereby the fetus and adult adapt to long-term, high altitude hypoxemia. In addition, we will examine several of these mechanisms in association with development of the fetus into an adult. This proposal is a broadly based, multidisciplinary program which uses physiologic, pharmacologic, biochemical, and molecular approaches to explore adaptations of the cardiovascular system, the cerebral blood vessels, uterine vessels, the fetal hypothalamic-pituitary-adrenal axis, and the myometrium in response to long-term hypoxemia. These studies will be conducted in fetal and adult sheep acclimatized to high altitude (3820 m/12,470 feet,) and in normoxic controls. They are based on eleven years of research by our group on the responses and acclimatization to high altitude hypoxia in the fetus and adult. The proposed studies examine a number of hypotheses regarding physiologic, biochemical, and molecular mechanisms. For example, in the heart we will test hypotheses regarding the roles of calcium channels, Ca2+-induced Ca2+ release, beta-receptor coupling to protein kinase A, and troponin and myosin ATPase isoforms in the responses to long-term hypoxemia. In the cerebral arteries we will test hypotheses regarding alpha adrenergic receptor subtypes, their coupling to second messengers, the relation to intracellular calcium modulation by protein kinase C the role of Ca2+ and K+ channels, vascular innervation, norepinephrine release and reuptake, relaxation mechanisms, et cetera, to long-term hypoxemia. In uterine arteries we will test several hypotheses regarding the mechanisms of modulation by cortisol, and how these mechanisms are altered by long-term hypoxemia. Finally, we also will test several hypotheses regarding the fetal hypothalamic-pituitary- adrenal responses to long-term hypoxemia, e.g., the role of adrenal adenylate cyclase, and glucocorticoid receptors, as well as signal transduction mechanisms in the myometrium. From a scientific standpoint, these studies will augment our understanding of the mechanisms whereby the fetus and adult successfully adapt to chronic hypoxemia. In addition, they will shed light on a number of aspects of development from fetus to adult. From a clinical standpoint, these studies relate to the problems of prolonged hypoxemia and successful high altitude acclimatization. For the fetus and newborn they also relate to responses to prolonged hypoxemia as occurs in women who live at high altitude, as well as those who smoke or are exposed to environmental pollution, as well as those who are anemic, or who have heart or lung disease or with """"""""placental insufficiency."""""""" For the newborn infant these studies relate to problems such as pulmonary hypertension, persistent fetal circulation, altered cerebrovascular function, and intracerebral hemorrhage. Finally, the studies give promise of shedding light on the mechanisms of the Barker hypotheses of prenatal programming of adult disease.
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