The overall theme of this proposal is to explore fundamental mechanisms whereby the fetus and adult acclimatize to high altitude, long-term hypoxia (LTH). In addition, we will examine several of these mechanisms in association with development. This proposal is a broadly based, multidisciplinary, integrated program using physiologic, pharmacologic, cellular, biochemical, and molecular approaches. Based on >16 years of research by our group, studies will be conducted in sheep acclimatized to high altitude (3820 m/12,470 ft). We shall examine a number of hypotheses. For example, in cerebral arteries we will test hypotheses regarding signal transduction mechanisms for both calcium (Ca2+)-independent and Ca2+-dependent regulation of thin and thick myofilament, e.g., the roles of protein kinase C (PKC), extracellular signal regulated kinases (ERKs), alpha adrenergic receptor subtypes, coupling to second messengers, Rho/Rho kinase, protein kinase G (PKG), and downstream effector proteins. We will test several hypotheses in regards to cerebral and pulmonary artery plasmalemmal Ca2+-activated K+ channels, their phosphorylation states and/or splice variants. In addition, we will explore the role of perivascular nerves in regulating cerebrovascular reactivity. In pregnant and nonpregnant uterine arteries, we will examine mechanisms of LTH modulation of PKC-ERK and related interactions. Finally, we will explore how LTH alters fetal hypothalamic-pituitary-adrenal responses, including the role of hypothalamic drive, pituitary responsiveness, and glucocorticoid synthesis. Scientifically the studies will augment our understanding of mechanisms whereby the fetus and adult acclimatize to chronic hypoxia. 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 at least three important problems. 1) For the fetus and newborn they relate to prolonged hypoxia as occurs in women who live at high altitude, as well as those who smoke or are exposed to environmental pollution, those who are anemic, or who have heart or lung disease, or with """"""""placental insufficiency."""""""" For the newborn they relate to altered cerebrovascular blood flow with intracerebral hemorrhage and pulmonary hypertension. 2) The studies also will contribute to understanding mechanisms of prenatal """"""""programming"""""""" of adult disease. 3) Finally, the studies are relevant to understanding mechanisms of diseases in adults and children, e.g., Acute Mountain Sickness, Preeclampsia, and High Altitude Cerebral and Pulmonary Edema.
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