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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD031226-18
Application #
8381849
Study Section
Special Emphasis Panel (ZHD1-DSR-A)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
18
Fiscal Year
2012
Total Cost
$214,178
Indirect Cost
$69,986
Name
Loma Linda University
Department
Type
DUNS #
009656273
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
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

Showing the most recent 10 out of 173 publications