Intrauterine chronic hypoxia and ryanodine receptors in fetal pulmonary arteries

Summary

Principal Investigator: Sean M Wilson
Abstract: DESCRIPTION (provided by applicant): Intrauterine stress can induce long-lived changes in function that predispose the fetus for disease throughout life. Maternal hypoxemia due to high altitude living, placental insufficiency, and smoking puts infants of certain populations at risk o developing pulmonary hypertension, high altitude pulmonary edema, and increases the risk for development of idiopathic pulmonary hypertension later in life. Gestation at high altitude causes a variety of pulmonary vascular malformations in fetal sheep including suppressed endothelium dependent relaxation, altered myocyte growth, and reactivity that place them at risk of developing hypertension after birth. Indeed, high altitude gestation and birth exaggerates hypoxia induced pulmonary vasoconstriction in 2 week old sheep and results in significant penetration of pulmonary hypertension. Sheep are therefore a relevant model for understanding novel pathways and mechanisms associated with fetal origins of pulmonary vascular disease because hypoxemia due to high altitude gestation recapitulates disease found in humans. The fundamental focus is that ryanodine receptors (RyR) are central to the process of pulmonary arterial constriction in response to acute alveolar hypoxia, which can be dysregulated in individuals with pulmonary hypertension. Three RyR isoforms are known, and all three are vital to the intrinsic vasoconstrictor response to acute hypoxia in pulmonary arteries. RyR channelopathies actively participate in the pathogenesis of neuronal, skeletal muscle, cardiac, and vascular diseases and yet their role in fetal programming of pulmonary vascular disease is unknown. The central hypothesis of this project is that high altitude gestation will suppress RyR-mediated local Ca2+ "sparks" and global Ca2+ responses due to acute hypoxia and that these responses will be manifested by reductions in RyR expression. We propose this counterbalances mechanisms that would increase vascular contraction to acute hypoxia. This would help reduce the extent of pulmonary hypertension due to long-term intrauterine hypoxia. The central hypothesis is based on published and preliminary studies performed with full-term fetal sheep. We plan to test our central hypothesis by pursuing two Specific Aims. Specific Aim 1 will determine whether high altitude gestation suppresses the expression of the three RyR isoforms. Specific Aim 2 will determine the corresponding reduction in RyR mediated Ca2+ responses and pulmonary vasoconstriction in response to acute hypoxia. The hypotheses will be examined by performing molecular, histochemical, and functional studies in pulmonary arteries from term-fetal lambs. With regards to the expected outcomes, the work proposed is expected to identify the influence of long-term intrauterine hypoxia on RyR function in the fetus. These studies are expected to fundamentally advance the field of pulmonary vascular biology by associating RyRs with pulmonary vascular disease. Such results will provide an important positive impact, because RyRs are highly likely to provide novel targets for therapeutic interventions in the treatment of pulmonary vascular disease.
Funding Period: 2012-06-01 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. pmc Chronic hypoxia suppresses pregnancy-induced upregulation of large-conductance Ca2+-activated K+ channel activity in uterine arteries
    Xiang Qun Hu
    Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University, School of Medicine, Loma Linda, CA 92350, USA
    Hypertension 60:214-22. 2012
  2. pmc Maternal high-altitude hypoxia and suppression of ryanodine receptor-mediated Ca2+ sparks in fetal sheep pulmonary arterial myocytes
    Scott R Hadley
    Center for Perinatal Biology, Loma Linda University, California 92350, USA
    Am J Physiol Lung Cell Mol Physiol 303:L799-813. 2012
  3. pmc Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs
    Arlin B Blood
    Department of Pediatrics, Division of Neonatology, Loma Linda University School of Medicine, Loma Linda, CA 92373, USA
    Am J Physiol Regul Integr Comp Physiol 304:R136-46. 2013
  4. pmc Chronic hypoxia inhibits pregnancy-induced upregulation of SKCa channel expression and function in uterine arteries
    Ronghui Zhu
    Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University, School of Medicine, Loma Linda, CA 92350, USA
    Hypertension 62:367-74. 2013
  5. ncbi Antenatal hypoxia and pulmonary vascular function and remodeling
    Demosthenes G Papamatheakis
    Center for Perinatal Biology, Loma Linda University School of Medicine, 11234 Anderson Street, Loma Linda, 92350 CA, USA
    Curr Vasc Pharmacol 11:616-40. 2013
  6. pmc Chronic hypoxia during gestation enhances uterine arterial myogenic tone via heightened oxidative stress
    Daliao Xiao
    Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, United States of America
    PLoS ONE 8:e73731. 2013

Detail Information

Publications6

  1. pmc Chronic hypoxia suppresses pregnancy-induced upregulation of large-conductance Ca2+-activated K+ channel activity in uterine arteries
    Xiang Qun Hu
    Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University, School of Medicine, Loma Linda, CA 92350, USA
    Hypertension 60:214-22. 2012
    ....
  2. pmc Maternal high-altitude hypoxia and suppression of ryanodine receptor-mediated Ca2+ sparks in fetal sheep pulmonary arterial myocytes
    Scott R Hadley
    Center for Perinatal Biology, Loma Linda University, California 92350, USA
    Am J Physiol Lung Cell Mol Physiol 303:L799-813. 2012
    ..The influence of both ontogeny and LTH on RyR-dependent cell excitability shed new light on the therapeutic potential of these channels for the treatment of pulmonary vascular disease in newborns as well as adults...
  3. pmc Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs
    Arlin B Blood
    Department of Pediatrics, Division of Neonatology, Loma Linda University School of Medicine, Loma Linda, CA 92373, USA
    Am J Physiol Regul Integr Comp Physiol 304:R136-46. 2013
    ..We conclude that chronic hypoxia in utero results in increased vasopressor response to both acute hypoxia and serotonin, but that rho-kinase is involved only in the increased response to serotonin...
  4. pmc Chronic hypoxia inhibits pregnancy-induced upregulation of SKCa channel expression and function in uterine arteries
    Ronghui Zhu
    Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University, School of Medicine, Loma Linda, CA 92350, USA
    Hypertension 62:367-74. 2013
    ..The findings suggest a novel mechanism of SKCa channels in regulating myogenic adaptation of uterine arteries in pregnancy and in the maladaptation of uteroplacental circulation caused by chronic hypoxia during gestation...
  5. ncbi Antenatal hypoxia and pulmonary vascular function and remodeling
    Demosthenes G Papamatheakis
    Center for Perinatal Biology, Loma Linda University School of Medicine, 11234 Anderson Street, Loma Linda, 92350 CA, USA
    Curr Vasc Pharmacol 11:616-40. 2013
    ....
  6. pmc Chronic hypoxia during gestation enhances uterine arterial myogenic tone via heightened oxidative stress
    Daliao Xiao
    Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, United States of America
    PLoS ONE 8:e73731. 2013
    ....

Research Grants30

  1. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  2. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  3. Signaling Mechanisms for Hypoxic Pulmonary Vasoconstriction
    Yong Xiao Wang; Fiscal Year: 2013
    ..Our data may also help to identify novel therapeutic targets for pulmonary hypertension and other related lung diseases. ..
  4. Peptide Therapy for Pulmonary Arterial Hypertension
    Jawaharlal M Patel; Fiscal Year: 2013
    ..Confirmation of the mechanism-based physiological approach for NO releasing PDE5 inhibitor function of this novel peptide in preclinical animal model is innovative for progression towards Phase I clinical trial for treatment of PH. ..
  5. TRP Channel-Dependent Regulation of Arterial Tone
    Scott Earley; Fiscal Year: 2013
    ..abstract_text> ..
  6. Mechanisms of Health Effects of Exercise in Children
    Dan M Cooper; Fiscal Year: 2013
    ..Collectively, the PPG will promote novel preventive and adjunctive exercise therapies in children with chronic inflammation- therapies grounded in a firm understanding of biological mechanisms. ..
  7. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  8. Cerebral Artery Alpha1 Adrenergic and PKC Regulatory Mechanisms
    Lawrence D Longo; Fiscal Year: 2013
    ....
  9. Vascular Smooth Muscle Function in Pulmonary Hypertension
    Nikki L Jernigan; Fiscal Year: 2013
    ..Ultimately, such knowledge has the potential to provide new directions in pulmonary hypertension therapy. ..
  10. Role of natriuretic peptides in the ductus arteriosus
    JOHN JEFFREY REESE; Fiscal Year: 2013
    ..abstract_text> ..
  11. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  12. REGULATION OF PULMONARY CIRCULATION IN FETUS AND NEWBORN
    Girija G Konduri; Fiscal Year: 2013
    ..These studies will identify an important new source of oxidative stress in PPHN. These observation may lead to new targeted therapies to improve vasodilation and oxygenation in PPHN. ..
  13. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..