DEVELOPMENTAL REGULATION OF O2 SENSING IN THE LUNG
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
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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...
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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...
- Inhibiting NF-κB in the developing lung disrupts angiogenesis and alveolarizationCristiana 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....
- Hypoxia-inducible factor-1α regulates KCNMB1 expression in human pulmonary artery smooth muscle cellsYong 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...
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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...
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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...
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Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN 55455, USA
Proc Natl Acad Sci U S A 104:18789-94. 2007....
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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...
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Department of Pediatrics, Division of Pediatric Pulmonary and Critical Care Medicine, University of Minnesota, Minneapolis, MN 55455, USA
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Bethel University, St Paul, MN 55112, USA
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- Chronic intrauterine pulmonary hypertension selectively modifies pulmonary artery smooth muscle cell gene expressionErnesto 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....
- Oxygen tension modulates the expression of pulmonary vascular BKCa channel alpha- and beta-subunitsErnesto 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...
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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...