DEVELOPMENTAL REGULATION OF O2 SENSING IN THE LUNG

Summary

Principal Investigator: David Cornfield
Abstract: DESCRIPTION (provided by applicant): At birth, pulmonary vasodilation occurs in association with an increase in oxygen tension. When pulmonary artery (PA) pressure does not decrease, persistent pulmonary hypertension of the newborn (PPHN) results. PPHN is characterized by increased pulmonary vascular tone and reactivity, and an incomplete response to perinatal vasodilator stimuli, including oxygen. Data from our laboratory have demonstrated that the pulmonary circulation responds to an acute increase in oxygen tension via calcium-sensitive K+ channel (BKCa) activation mediated by Ca2+ release from a developmentally regulated ryanodine-sensitive store. Despite the critical importance of oxygen in mediating perinatal pulmonary vasodilation, how oxygen sensing is compromised in PPHN remains unknown. Preliminary data indicate that in an ovine model of PPHN, pulmonary artery smooth muscle cell (PA SMC) BKCa channel expression, oxygen sensing and intracellular cellular Ca2+ homeostasis are compromised. The present proposal tests the working hypothesis that in an animal model of PPHN, pulmonary artery smooth muscle cell oxygen sensing is compromised, thereby attenuating perinatal pulmonary vasodilation. The specific aims are to test the hypotheses that in an ovine model of perinatal pulmonary hypertension: Aim 1. O2 sensing is compromised through both direct and indirect effects on BKCa channel activation;and Aim 2. BKCa channel subunit expression modulates PA SMC O2 sensing. The studies proposed in the present application will determine whether the attenuated response of the pulmonary circulation to vasodilator stimuli, the hallmark of PPHN, results from compromised PA SMC BKCa expression and/or function. Completion of the proposed studies may identify specific molecular target for the development of novel K+ channel based strategies to address a profoundly difficult clinical problem. The strategy of modulating BKCa channel subunit expression to enhance pulmonary vasodilation may be more broadly applicable to other vascular diseases.
Funding Period: 1999-09-30 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. pmc Hypoxia-inducible factor-1α in pulmonary artery smooth muscle cells lowers vascular tone by decreasing myosin light chain phosphorylation
    Yu Mee Kim
    Department of Pediatrics, Stanford University Medical School, Stanford, CA 94305, USA
    Circ Res 112:1230-3. 2013
  2. pmc Voltage-dependent anion channel-2 interaction with nitric oxide synthase enhances pulmonary artery endothelial cell nitric oxide production
    Cristina M Alvira
    Center of Excellence in Pulmonary Biology, Divisions of Pediatric Pulmonary, Asthma and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
    Am J Respir Cell Mol Biol 47:669-78. 2012
  3. pmc Inhibiting NF-κB in the developing lung disrupts angiogenesis and alveolarization
    Cristiana Iosef
    Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305 5208, USA
    Am J Physiol Lung Cell Mol Physiol 302:L1023-36. 2012
  4. pmc Hypoxia-inducible factor-1α regulates KCNMB1 expression in human pulmonary artery smooth muscle cells
    Yong Tae Ahn
    Ctr for Excellence in Pulmonary Biology, Division of Pediatric Pulmonary, Asthma and Critical Care Medicine, Stanford Univ Medical School Medicine, Stanford, CA 94305, USA
    Am J Physiol Lung Cell Mol Physiol 302:L352-9. 2012
  5. pmc Rho kinase modulates postnatal adaptation of the pulmonary circulation through separate effects on pulmonary artery endothelial and smooth muscle cells
    Cristina M Alvira
    Center for Excellence in Pulmonary Biology, Dept of Pediatrics, Stanford Univ Medical School, CA 94305, USA
    Am J Physiol Lung Cell Mol Physiol 299:L872-8. 2010
  6. ncbi Utility of blood cultures in postoperative pediatric intensive care unit patients
    Andrew W Kiragu
    Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University, Stanford, CA, USA
    Pediatr Crit Care Med 10:364-8. 2009
  7. pmc Developmental regulation of hypoxia-inducible factor 1 and prolyl-hydroxylases in pulmonary vascular smooth muscle cells
    Ernesto R Resnik
    Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN 55455, USA
    Proc Natl Acad Sci U S A 104:18789-94. 2007
  8. ncbi Chronic intrauterine pulmonary hypertension increases capacitative calcium entry in fetal pulmonary artery smooth muscle cells
    Ernesto R Resnik
    Division of Pediatric Pulmonary and Critical Care Medicine, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
    Am J Physiol Lung Cell Mol Physiol 292:L953-9. 2007
  9. ncbi Acute normoxia increases fetal pulmonary artery endothelial cell cytosolic Ca2+ via Ca2+-induced Ca2+ release
    Raz Tirosh
    Department of Pediatrics, Division of Pediatric Pulmonary and Critical Care Medicine, University of Minnesota, Minneapolis, MN 55455, USA
    Pediatr Res 60:258-63. 2006
  10. ncbi Lung specific developmental expression of the Xenopus laevis surfactant protein C and B genes
    Brian A Hyatt
    Bethel University, St Paul, MN 55112, USA
    Gene Expr Patterns 7:8-14. 2007

Scientific Experts

  • Ernesto Resnik
  • David N Cornfield
  • Cristina M Alvira
  • Shu Chen Lyu
  • Yu Mee Kim
  • David J Sukovich
  • Lihua Ying
  • Cristiana Iosef
  • Yanli Hou
  • Yong Tae Ahn
  • Andrew W Kiragu
  • Brian A Hyatt
  • Raz Tirosh
  • Jean Herron
  • Maggie Keck
  • Elizabeth A Barnes
  • Sushma Reddy
  • Chihhsin Chen
  • Cristiana Husted
  • Eloa S Adams
  • Eloa Adams
  • Jeffrey Nowak
  • Anita Umesh
  • Tero Pekka Alastalo
  • Judith Zier
  • Natalie S Johnson
  • Jamie L Lohr
  • Zhigang Hong
  • E Kenneth Weir
  • Bradley Linden
  • Franklin Anderson

Detail Information

Publications13

  1. pmc Hypoxia-inducible factor-1α in pulmonary artery smooth muscle cells lowers vascular tone by decreasing myosin light chain phosphorylation
    Yu Mee Kim
    Department of Pediatrics, Stanford University Medical School, Stanford, CA 94305, USA
    Circ Res 112:1230-3. 2013
    ..Although acute hypoxia causes pulmonary vasoconstriction and chronic hypoxia can cause vascular remodeling and pulmonary hypertension, conflicting data exist on the role of HIF-1α in modulating pulmonary vascular tone...
  2. pmc Voltage-dependent anion channel-2 interaction with nitric oxide synthase enhances pulmonary artery endothelial cell nitric oxide production
    Cristina M Alvira
    Center of Excellence in Pulmonary Biology, Divisions of Pediatric Pulmonary, Asthma and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
    Am J Respir Cell Mol Biol 47:669-78. 2012
    ..We speculate that decreases in VDAC2 may contribute to the limited eNOS activity that characterizes pulmonary hypertension...
  3. pmc Inhibiting NF-κB in the developing lung disrupts angiogenesis and alveolarization
    Cristiana Iosef
    Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305 5208, USA
    Am J Physiol Lung Cell Mol Physiol 302:L1023-36. 2012
    ....
  4. pmc Hypoxia-inducible factor-1α regulates KCNMB1 expression in human pulmonary artery smooth muscle cells
    Yong Tae Ahn
    Ctr for Excellence in Pulmonary Biology, Division of Pediatric Pulmonary, Asthma and Critical Care Medicine, Stanford Univ Medical School Medicine, Stanford, CA 94305, USA
    Am J Physiol Lung Cell Mol Physiol 302:L352-9. 2012
    ..We speculate that selective modulation of KCNMB1 expression may serve as a novel therapeutic approach to address diseases characterized by an increase in vascular tone...
  5. pmc Rho kinase modulates postnatal adaptation of the pulmonary circulation through separate effects on pulmonary artery endothelial and smooth muscle cells
    Cristina M Alvira
    Center for Excellence in Pulmonary Biology, Dept of Pediatrics, Stanford Univ Medical School, CA 94305, USA
    Am J Physiol Lung Cell Mol Physiol 299:L872-8. 2010
    ..ROCK inhibition may represent a novel treatment strategy for neonatal pulmonary vascular disease...
  6. ncbi Utility of blood cultures in postoperative pediatric intensive care unit patients
    Andrew W Kiragu
    Department of Pediatrics, Center for Excellence in Pulmonary Biology, Stanford University, Stanford, CA, USA
    Pediatr Crit Care Med 10:364-8. 2009
    ..To determine the frequency of positive blood cultures in patients with fevers in the initial 48-hour postoperative period...
  7. pmc Developmental regulation of hypoxia-inducible factor 1 and prolyl-hydroxylases in pulmonary vascular smooth muscle cells
    Ernesto R Resnik
    Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN 55455, USA
    Proc Natl Acad Sci U S A 104:18789-94. 2007
    ....
  8. ncbi Chronic intrauterine pulmonary hypertension increases capacitative calcium entry in fetal pulmonary artery smooth muscle cells
    Ernesto R Resnik
    Division of Pediatric Pulmonary and Critical Care Medicine, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
    Am J Physiol Lung Cell Mol Physiol 292:L953-9. 2007
    ..Transient receptor potential channel gene expression was greater in control compared with PHTN PA SMC. PHTN may compromise perinatal pulmonary vasodilation, in part, by modulating PA SMC CCE...
  9. ncbi Acute normoxia increases fetal pulmonary artery endothelial cell cytosolic Ca2+ via Ca2+-induced Ca2+ release
    Raz Tirosh
    Department of Pediatrics, Division of Pediatric Pulmonary and Critical Care Medicine, University of Minnesota, Minneapolis, MN 55455, USA
    Pediatr Res 60:258-63. 2006
    ....
  10. ncbi Lung specific developmental expression of the Xenopus laevis surfactant protein C and B genes
    Brian A Hyatt
    Bethel University, St Paul, MN 55112, USA
    Gene Expr Patterns 7:8-14. 2007
    ..laevis, xSP-C and xSP-B are expressed only in lung. Knowledge of the sequence and expression pattern of these two surfactant proteins in Xenopus might allow for use of this organism to study early lung development...
  11. ncbi Chronic intrauterine pulmonary hypertension selectively modifies pulmonary artery smooth muscle cell gene expression
    Ernesto Resnik
    Dept of Pediatrics, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94304, USA
    Am J Physiol Lung Cell Mol Physiol 290:L426-33. 2006
    ....
  12. ncbi Oxygen tension modulates the expression of pulmonary vascular BKCa channel alpha- and beta-subunits
    Ernesto Resnik
    Univ of Minnesota, Minneapolis, MN 55455, USA
    Am J Physiol Lung Cell Mol Physiol 290:L761-L768. 2006
    ..Together, these results suggest that oxygen tension modulates BK(Ca) channel subunit mRNA expression, and the regulation is, at least in part, at the transcriptional level...
  13. ncbi Oxygen increases ductus arteriosus smooth muscle cytosolic calcium via release of calcium from inositol triphosphate-sensitive stores
    Maggie Keck
    Div of Pediatric Pulmonary and Critical Care Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA
    Am J Physiol Lung Cell Mol Physiol 288:L917-23. 2005
    ..Prolonged patency of the DA may result from disordered intracellular calcium homeostasis...