The overall theme of this proposal is to explore fundamental mechanisms whereby the mother and her fetus acclimatize to high altitude, long-term hypoxia. In addition, we will examine the mechanisms in association with development from fetus to adult. Hypoxia is one of the most common and severe stresses to an organism's homeostatic mechanisms and hypoxia during gestation have profound adverse effects on maternal health and developmental plasticity. Much remains unknown of the molecular mechanisms in response to long-term hypoxia in both the fetus and adult. This proposal is a broadly based, multidisciplinary, integrated program using physiological, pharmacological, cellular, biochemical, and molecular approaches. Based on >25 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, long-term hypoxia during gestation results in epigenetic-mediated molecular modifications of systemic and cellular and sub-cellular responses in the mother and her fetus, significantly impacting developmental plasticity and the subsequent risk for disease. In uterine arteries, we will test the hypothesis tht steroid hormone-induced dynamic, epigenetic-mediated changes of DNA methylation and demethylation play a key role in regulating expression and function of large- conductance Ca2+-activated K+ channels in uterine vascular adaptation to pregnancy and chronic hypoxia. In cerebral arteries, we will test the hypothesis that epigenetic-related mechanisms such as DNA methylation, histone modifications and microRNA play a key role in regulating expression and function of ?1-adrenoceptor subtypes in cerebral arteries in response to development and chronic hypoxia. We will determine the role of ?1- adrenoceptor subtypes in sympathetic system-mediated regulation of cerebral blood flow, as well as to examine the effects of inhibitors of DNA methylation, histone modification and microRNA on ?1-adrenoceptor subtype- mediated cerebral blood flow regulation in normoxic and high altitude hypoxic fetus and adult sheep. In addition, we will test the hypothesis that chronic hypoxia attenuates vascular contractility in general, and cerebrovascular contractility in particular, through down-regulation of myosin light chain kinase (MLCK) activity via a microRNA- mediated decrease in translation of MLCK message, an increase in proteosomal degradation of MLCK protein, and attenuation of MLCK specific activity. Finally, we will test the hypothesis that gestational hypoxia alters molecular ad epigenetic mechanisms in regulating signaling protein gene expression patterns, resulting in reprogramming of brown adipose tissue characteristics/function in perirenal adipose tissue of the developing fetus and lamb. Scientifically the proposed studies will augment our understanding of molecular and epigenetic mechanisms in regulating the expression and function of several important genes including ion channels, membrane receptors, key enzymes and signaling proteins in maternal and fetal vasculatures and adipose tissue in response to long-term hypoxia. 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 developmental programming of health and disease. 3) Finally, in the adult the studies are relevant to understanding mechanisms of diseases, including acute mountain sickness, preeclampsia, and high altitude cerebral and pulmonary edema.
Program Narrative Chronic hypoxia during gestation has profound adverse effects on maternal health and fetal developmental plasticity. Yet, much remains unknown of molecular mechanisms in the response to long-term hypoxia in both the fetus and adult. Scientifically, the studies will augment our understanding of basic mechanisms whereby the mother and fetus acclimatize to chronic hypoxia. From a clinical standpoint, these studies may provide new insights and suggest new directions in the clinical management of pregnancy complications and abnormal fetal development associated with gestational hypoxia, thereby reducing perinatal morbidity and mortality while improving maternal health and neonatal outcome.
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