The overall theme of this project is to understand whereby acclimatization to high altitude long-term hypoxia (LTH) alters fundamental mechanisms in the cerebrovasculature of the fetus and adult. We also will examine these mechanisms in association with development from fetus to adult. This project is broadly based, multidisciplinary, and vertically integrated using physiologic, cellular, biochemical, and molecular approaches. Based on two decades of research, we shall test a number of hypotheses in sheep acclimatized to high altitude. The overall hypothesis is that high altitude, long-term hypoxia is associated with changes in cerebrovascular contractile responses secondary to altered alphai-adrenergic-receptor (or AR) subtypes and/or specific protein kinase C isoforms (PKC)-mediated downstream Ca2+-dependent and Ca -independent signal transduction pathways. An associated hypothesis is that LTH significantly alters Oi-AR-subtype- and specific PKC isozyme-mediated expression of proto-oncogenes and genes representing vascular smooth muscle """"""""synthetic"""""""" and/or """"""""proliferative"""""""" phenotypes, as compared to those of adult """"""""contractile"""""""" phenotype.
Four specific aims will examine the role of LTH in cerebral artery Or adrenergic-mediated signal tranduction of thin and thick myofilament, e.g., 1) roles of Oi-AR, PKC isoforms, extracellular signal regulated kinases (ERKs), and downstream effector proteins, 2) the role of plasma membrane and sarcoplasmic reticulum Ca2+ channels, 3) gene regulation of vascular phenotypes, and 4) signaling pathways gene/protein discovery. For the studies we will utilize agonist-induced contractility and intracellular [Ca2+], Western immunobiots, RT-PCR, RNAi silencing, confocal microscopy, 2D-gel-mass spectroscopy, and gene microarray/pathways analysis. Scientifically the studies will augment our understanding of basic mechanisms whereby fetal and adult cerebral vessels acclimatize to LTH. They also will illustrate aspects of development from fetus to adult. Clinically the studies relate to at least three critical 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;for the newborn altered cerebrovascular blood flow with intracerebral hemorrhage and pulmonary hypertension. 2) They also will contribute to understanding mechanisms of cardiovascular disorders and renatal """"""""programming"""""""" of adult disease. 3) Finally, they are relevant to understanding mechanisms of diseases such as: Acute Mountain Sickness, Preeclampsia, and High Altitude Cerebral and Pulmonary Edema.
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|Myers, Dean A; Singleton, Krista; Kenkel, Christy et al. (2016) Gestational hypoxia modulates expression of corticotropin-releasing hormone and arginine vasopressin in the paraventricular nucleus in the ovine fetus. Physiol Rep 4:|
|Hu, Xiang-Qun; Huang, Xiaohui; Xiao, Daliao et al. (2016) Direct effect of chronic hypoxia in suppressing large conductance Ca(2+)-activated K(+) channel activity in ovine uterine arteries via increasing oxidative stress. J Physiol 594:343-56|
|Blum-Johnston, Carla; Thorpe, Richard B; Wee, Chelsea et al. (2016) Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth. Am J Physiol Lung Cell Mol Physiol 310:L271-86|
|Goyal, Ravi; Billings, Tara L; Mansour, Trina et al. (2016) Vitamin D status and metabolism in an ovine pregnancy model: effect of long-term, high-altitude hypoxia. Am J Physiol Endocrinol Metab 310:E1062-71|
|Vrancken, Kurt; Schroeder, Hobe J; Longo, Lawrence D et al. (2016) Postprandial lipids accelerate and redirect nitric oxide consumption in plasma. Nitric Oxide 55-56:70-81|
|Newby, Elizabeth A; Myers, Dean A; Ducsay, Charles A (2015) Fetal endocrine and metabolic adaptations to hypoxia: the role of the hypothalamic-pituitary-adrenal axis. Am J Physiol Endocrinol Metab 309:E429-39|
|Ma, Qingyi; Zhang, Lubo (2015) Epigenetic programming of hypoxic-ischemic encephalopathy in response to fetal hypoxia. Prog Neurobiol 124:28-48|
|Khorram, O; Chuang, T D; Pearce, W J (2015) Long-term effects of maternal undernutrition on offspring carotid artery remodeling: role of miR-29c. J Dev Orig Health Dis 6:342-9|
|Myers, Dean A; Singleton, Krista; Hyatt, Kim et al. (2015) Long-Term Gestational Hypoxia Modulates Expression of Key Genes Governing Mitochondrial Function in the Perirenal Adipose of the Late Gestation Sheep Fetus. Reprod Sci 22:654-63|
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