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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01HD031226-20
Application #
8704962
Study Section
Special Emphasis Panel (ZHD1)
Program Officer
Raju, Tonse N
Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Loma Linda University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Loma Linda
State
CA
Country
United States
Zip Code
92354
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
Liu, Taiming; Schroeder, Hobe J; Wilson, Sean M et al. (2016) Local and systemic vasodilatory effects of low molecular weight S-nitrosothiols. Free Radic Biol Med 91:215-23
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
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
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:
Mata-Greenwood, Eugenia; Jackson, P Naomi; Pearce, William J et al. (2015) Endothelial glucocorticoid receptor promoter methylation according to dexamethasone sensitivity. J Mol Endocrinol 55:133-46
Newby, Elizabeth A; Kaushal, Kanchan M; Myers, Dean A et al. (2015) Adrenocorticotropic Hormone and PI3K/Akt Inhibition Reduce eNOS Phosphorylation and Increase Cortisol Biosynthesis in Long-Term Hypoxic Ovine Fetal Adrenal Cortical Cells. Reprod Sci 22:932-41
Chuang, Tsai-Der; Pearce, William J; Khorram, Omid (2015) miR-29c induction contributes to downregulation of vascular extracellular matrix proteins by glucocorticoids. Am J Physiol Cell Physiol 309:C117-25
Adeoye, Olayemi O; Silpanisong, Jinjutha; Williams, James M et al. (2015) Role of the sympathetic autonomic nervous system in hypoxic remodeling of the fetal cerebral vasculature. J Cardiovasc Pharmacol 65:308-16
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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