The overall theme of this application is to explore fundamental mechanisms whereby the fetus and adult acclimatize to high altitude, long-term hypoxia (LTH). In addition, we will examine these mechanisms in association with development from fetus to adult. This application is a broadly based, multidisciplinary integrated program using physiologic, pharmacologic, cellular, biochemical, and molecular approaches. Based on >21 years of research by our group, studies will be conducted in sheep acclimatized to high altitude (3801 m/12,470 ft). We shall test a number of hypotheses. The overall hypothesis is that high altitude, LTH causes coordination of systemic, cellular, and subcellular responses in the mother and fetus, significantly impacting developmental plasticity and subsequent risk for disease. In cerebral arteries, we will test hypotheses regarding Oi-adrenergic-mediated signal transduction mechanisms for both Ca^*-dependent and Ca^^-independent regulation of thin and thick myofilament, e.g., roles of alphal adrenergic receptor subtypes, protein kinase C isoforms, extracellular signal regulated kinases, and coupling to downstream effectors. We will test the hypothesis that hypoxic acclimatization effects on arterial structure and function are mediated by vascular endothelial growth factor and its effects on the smooth muscle, endothelium, and perivascular nerves of fetal cerebral arteries. In addition, we will explore the role of perivascular nerves in cerebrovascular reactivity. In uterine arteries, we will examine mechanisms of steroid hormones in maladaptation of uterine circulation caused by LTH in pregnancy. Finally, we will explore how LTH alters the role of nitric oxide in the regulation of fetal adrenal Cortisol synthesis. Scientifically the studies will augment our understanding of mechanisms whereby fetus and adult acclimatize to LTH. In addition, they will shed light on a number of aspects of maturational development. From a clinical standpoint, these studies relate to at least three important problems. 1) For the fetus and newborn they relate to responses to prolonged hypoxia as occurs in women who live at high altitude, as well as those who smoke or are anemic, who have heart or lung disease, or with "placental insufficiency." For newborn they relate to altered cerebrovascular blood flow with intracerebral hemorrhage and pulmonary hypertension. 2) The studies also will contribute to understanding mechanisms of maternal cardiovascular disorders and prenatal "programming" of adult disease. 3) Finally, the studies are relevant to understanding mechanisms of diseases, including: Acute Mountain Sickness, Preeclampsia, and High Altitude Cerebral and Pulmonary Edema.
Scientifically, the studies will augment our understanding of basic mechanisms whereby fetus and adult acclimatize to chronic hypoxia. From a clinical standpoint, these studies relate to important problems: fetus and newborn responses to hypoxia as occurs in women at high altitude, as well as those who are anemic, or who have heart or lung disease, altered cerebrovascular blood flow with intracerebral hemorrhage and pulmonary hypertension, and mechanisms of maternal stress and prenatal "programming" understanding mechanisms of acute mountain sickness, preeclampsia, and high altitude cerebral and pulmonary edema.
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