The overall theme of this proposal is to explore fundamental mechanisms whereby the fetus and adult acclimatize to high altitude, long-term hypoxia (LTH). In addition, we will examine several of these mechanisms in association with development. This proposal is a broadly based, multidisciplinary, integrated program using physiologic, pharmacologic, cellular, biochemical, and molecular approaches. Based on >16 years of research by our group, studies will be conducted in sheep acclimatized to high altitude (3820 m/12,470 ft). We shall examine a number of hypotheses. For example, in cerebral arteries we will test hypotheses regarding signal transduction mechanisms for both calcium (Ca2+)-independent and Ca2+-dependent regulation of thin and thick myofilament, e.g., the roles of protein kinase C (PKC), extracellular signal regulated kinases (ERKs), alpha adrenergic receptor subtypes, coupling to second messengers, Rho/Rho kinase, protein kinase G (PKG), and downstream effector proteins. We will test several hypotheses in regards to cerebral and pulmonary artery plasmalemmal Ca2+-activated K+ channels, their phosphorylation states and/or splice variants. In addition, we will explore the role of perivascular nerves in regulating cerebrovascular reactivity. In pregnant and nonpregnant uterine arteries, we will examine mechanisms of LTH modulation of PKC-ERK and related interactions. Finally, we will explore how LTH alters fetal hypothalamic-pituitary-adrenal responses, including the role of hypothalamic drive, pituitary responsiveness, and glucocorticoid synthesis. Scientifically the studies will augment our understanding of mechanisms whereby the fetus and adult acclimatize to chronic hypoxia. In addition, they will shed light on a number of aspects of development from fetus to adult. From a clinical standpoint, these studies relate to at least three important problems. 1) For the fetus and newborn they relate to prolonged hypoxia as occurs in women who live at high altitude, as well as those who smoke or are exposed to environmental pollution, those who are anemic, or who have heart or lung disease, or with """"""""placental insufficiency."""""""" For the newborn they relate to altered cerebrovascular blood flow with intracerebral hemorrhage and pulmonary hypertension. 2) The studies also will contribute to understanding mechanisms of prenatal """"""""programming"""""""" of adult disease. 3) Finally, the studies are relevant to understanding mechanisms of diseases in adults and children, e.g., Acute Mountain Sickness, Preeclampsia, and High Altitude Cerebral and Pulmonary Edema.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-MCHG-B (LL))
Program Officer
Raju, Tonse N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Loma Linda University
Other Basic Sciences
Schools of Medicine
Loma Linda
United States
Zip Code
Liu, Taiming; Zhang, Meijuan; Terry, Michael H et al. (2018) Nitrite potentiates the vasodilatory signaling of S-nitrosothiols. Nitric Oxide 75:60-69
Pearce, William J (2018) Fetal Cerebrovascular Maturation: Effects of Hypoxia. Semin Pediatr Neurol 28:17-28
Pearce, W J (2018) A path well travelled may lead to better stroke recovery. Acta Physiol (Oxf) 223:e13061
Vargas, Vladimir E; Myers, Dean A; Kaushal, Kanchan M et al. (2018) Expression of StAR and Key Genes Regulating Cortisol Biosynthesis in Near Term Ovine Fetal Adrenocortical Cells: Effects of Long-Term Hypoxia. Reprod Sci 25:230-238
Chuang, Tsai-Der; Sakurai, Reiko; Gong, Ming et al. (2018) Role of miR-29 in Mediating Offspring Lung Phenotype in a Rodent Model of Intrauterine Growth Restriction. Am J Physiol Regul Integr Comp Physiol :
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
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
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:

Showing the most recent 10 out of 181 publications