REGULATION OF PULMONARY CIRCULATION IN FETUS AND NEWBORN

Summary

Principal Investigator: Girija G Konduri
Abstract: Project Summary Persistent pulmonary hypertension of the newborn (PPHN) is a condition that results from failure of pulmonary vasodilation to occur at birth. The affected infants are hypoxemic and have increased risks of mortality and long-term disabilities. Studies in a fetal lamb model of PPHN, induced by prenatal ductal constriction demonstrated a decrease in NO release and increase in oxidative stress in pulmonary arteries. Activation of NADPH oxidase and uncoupled activity of endothelial nitric oxide synthase (eNOS) are sources of superoxide (O2[unreadable]-) in the pulmonary arteries in PPHN. Mitochondrial oxygen consumption is an important source of O2[unreadable]- generation in vascular cells. Increase in O2 availability and oxidative phosphorylation at birth may lead to increased reactive oxygen species (ROS) in mitochondria. However, the contribution of mitochondrial ROS to oxidative stress in PPHN is unknown. Exposure to ATP, a NOS agonist, and postnatal oxygen tension stimulate the association of eNOS with the mitochondrial outer membrane protein, porin in normal fetal lamb pulmonary artery endothelial cells (PAEC). Targeted NO release in this location regulates the rate of oxidative phosphorylation to decrease O2[unreadable]- production in normal fetal PAEC. The expression of manganese superoxide dismutase (MnSOD) is also decreased in PPHN. We propose to investigate the novel hypothesis that decreased targeting of eNOS to mitochondrial outer membrane and decreased expression of MnSOD lead to excess generation and decreased quenching of mitochondrial O2[unreadable]-. The mitochondrial O2[unreadable]- in turn impairs pulmonary vasodilation at birth. The broad specific aims of the proposed studies are to (1) Investigate the alterations in eNOS-mitochondrial interactions and MnSOD expression in PPHN and its effect on O2 consumption, NO and O2[unreadable]- levels during postnatal transition of PAEC, (2) Investigate the mechanism of altered eNOS targeting to mitochondria in PPHN and (3) investigate the role of mitochondrial oxidative stress in the impaired pulmonary vasodilation and oxygenation during birth-related transition in PPHN. Studies will be done in PAEC and pulmonary arteries harvested from lambs with prenatal ligation of ductus arteriosus (PPHN) and in sham ligation controls. Studies will be also done in intact fetal lambs with or without PPHN delivered at term to investigate the role of mitochondrial O2[unreadable]- in the transition of pulmonary circulation and oxygenation at birth. 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.
Funding Period: 1998-05-01 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension
    Girija G Konduri
    Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53201 1997, USA
    Am J Physiol Heart Circ Physiol 292:H1812-20. 2007
  2. pmc Antenatal betamethasone improves postnatal transition in late preterm lambs with persistent pulmonary hypertension of the newborn
    Girija G Konduri
    Department of Pediatrics, Children s Research Institute and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    Pediatr Res 73:621-9. 2013
  3. pmc AMP kinase activation improves angiogenesis in pulmonary artery endothelial cells with in utero pulmonary hypertension
    Ru Jeng Teng
    Department of Pediatrics, Medical College of Wisconsin, Milwaukee, USA
    Am J Physiol Lung Cell Mol Physiol 304:L29-42. 2013
  4. pmc Decreases in manganese superoxide dismutase expression and activity contribute to oxidative stress in persistent pulmonary hypertension of the newborn
    Adeleye J Afolayan
    Department of Pediatrics, Cardiovascular Research Center and Children s Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    Am J Physiol Lung Cell Mol Physiol 303:L870-9. 2012
  5. pmc Cross talk between NADPH oxidase and autophagy in pulmonary artery endothelial cells with intrauterine persistent pulmonary hypertension
    Ru Jeng Teng
    Div of Neonatology, Dept of Pediatrics, Medical College of Wisconsin, Wauwatosa, WI 53226, USA
    Am J Physiol Lung Cell Mol Physiol 302:L651-63. 2012
  6. pmc Sepiapterin improves angiogenesis of pulmonary artery endothelial cells with in utero pulmonary hypertension by recoupling endothelial nitric oxide synthase
    Ru Jeng Teng
    Division of Neonatology, Dept of Pediatrics, Medical College of Wisconsin, Suite C410, Children Corporate Center, 999N 92nd St, Wauwatosa, WI 53226, USA
    Am J Physiol Lung Cell Mol Physiol 301:L334-45. 2011
  7. pmc Nitrotyrosine impairs angiogenesis and uncouples eNOS activity of pulmonary artery endothelial cells isolated from developing sheep lungs
    Ru Jeng Teng
    Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin 53226, USA
    Pediatr Res 69:112-7. 2011
  8. pmc Impaired voltage gated potassium channel responses in a fetal lamb model of persistent pulmonary hypertension of the newborn
    Girija G Konduri
    Department of Pediatrics, Medical College of Wisconsin and Zablocki VA Medical Center, Milwaukee, Wisconsin 53226, USA
    Pediatr Res 66:289-94. 2009
  9. pmc Advances in the diagnosis and management of persistent pulmonary hypertension of the newborn
    G Ganesh Konduri
    Department of Pediatrics, Division of Neonatology, Children s Research Institute and Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Pediatr Clin North Am 56:579-600, Table of Contents. 2009
  10. pmc Increased superoxide production contributes to the impaired angiogenesis of fetal pulmonary arteries with in utero pulmonary hypertension
    Ru Jeng Teng
    Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin 53226, USA
    Am J Physiol Lung Cell Mol Physiol 297:L184-95. 2009

Detail Information

Publications13

  1. ncbi Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension
    Girija G Konduri
    Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53201 1997, USA
    Am J Physiol Heart Circ Physiol 292:H1812-20. 2007
    ..HSP90 immunoprecipitated from PPHN pulmonary arteries had increased nitrotyrosine signal. Oxidant stress from uncoupled eNOS contributes to impaired pulmonary vasodilation in PPHN induced by ductal ligation in fetal lambs...
  2. pmc Antenatal betamethasone improves postnatal transition in late preterm lambs with persistent pulmonary hypertension of the newborn
    Girija G Konduri
    Department of Pediatrics, Children s Research Institute and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    Pediatr Res 73:621-9. 2013
    ..Betamethasone decreases the oxidative stress and improves antioxidant balance in PPHN. We investigated whether antenatal betamethasone improves pulmonary vasodilation and postnatal oxygenation in late preterm lambs with PPHN...
  3. pmc AMP kinase activation improves angiogenesis in pulmonary artery endothelial cells with in utero pulmonary hypertension
    Ru Jeng Teng
    Department of Pediatrics, Medical College of Wisconsin, Milwaukee, USA
    Am J Physiol Lung Cell Mol Physiol 304:L29-42. 2013
    ..In conclusion, activation of AMPK restores angiogenesis and increases the bioavailability of nitric oxide in IPH. Whether Metformin is beneficial in the management of pulmonary hypertension requires further investigation...
  4. pmc Decreases in manganese superoxide dismutase expression and activity contribute to oxidative stress in persistent pulmonary hypertension of the newborn
    Adeleye J Afolayan
    Department of Pediatrics, Cardiovascular Research Center and Children s Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    Am J Physiol Lung Cell Mol Physiol 303:L870-9. 2012
    ..Our observations suggest that decreased MnSOD expression and activity contribute to the endothelial dysfunction observed in PPHN...
  5. pmc Cross talk between NADPH oxidase and autophagy in pulmonary artery endothelial cells with intrauterine persistent pulmonary hypertension
    Ru Jeng Teng
    Div of Neonatology, Dept of Pediatrics, Medical College of Wisconsin, Wauwatosa, WI 53226, USA
    Am J Physiol Lung Cell Mol Physiol 302:L651-63. 2012
    ..Our results suggest that, in PPHN-PAEC, a positive feedback relationship between autophagy and NOX activity may regulate angiogenesis...
  6. pmc Sepiapterin improves angiogenesis of pulmonary artery endothelial cells with in utero pulmonary hypertension by recoupling endothelial nitric oxide synthase
    Ru Jeng Teng
    Division of Neonatology, Dept of Pediatrics, Medical College of Wisconsin, Suite C410, Children Corporate Center, 999N 92nd St, Wauwatosa, WI 53226, USA
    Am J Physiol Lung Cell Mol Physiol 301:L334-45. 2011
    ..Increasing BH4 levels via Sep supplementation may be an important therapy for improving eNOS function and restoring angiogenesis in PPHN...
  7. pmc Nitrotyrosine impairs angiogenesis and uncouples eNOS activity of pulmonary artery endothelial cells isolated from developing sheep lungs
    Ru Jeng Teng
    Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin 53226, USA
    Pediatr Res 69:112-7. 2011
    ..Because NO plays an important role in angiogenesis and vasodilation, these observations suggest a mechanism for the impaired vasodilation and angiogenesis during sepsis in the developing lung...
  8. pmc Impaired voltage gated potassium channel responses in a fetal lamb model of persistent pulmonary hypertension of the newborn
    Girija G Konduri
    Department of Pediatrics, Medical College of Wisconsin and Zablocki VA Medical Center, Milwaukee, Wisconsin 53226, USA
    Pediatr Res 66:289-94. 2009
    ..Oxidative stress impairs Kv channel function in PPHN. Superoxide scavengers may improve pulmonary vasodilation in PPHN in part by restoring Kv channel function...
  9. pmc Advances in the diagnosis and management of persistent pulmonary hypertension of the newborn
    G Ganesh Konduri
    Department of Pediatrics, Division of Neonatology, Children s Research Institute and Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Pediatr Clin North Am 56:579-600, Table of Contents. 2009
    ..This review focuses on the diagnosis, recent advances in management, and recommendations for the long-term follow-up of infants who have PPHN...
  10. pmc Increased superoxide production contributes to the impaired angiogenesis of fetal pulmonary arteries with in utero pulmonary hypertension
    Ru Jeng Teng
    Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Wauwatosa, Wisconsin 53226, USA
    Am J Physiol Lung Cell Mol Physiol 297:L184-95. 2009
    ..Our data suggest that PPHN is associated with increased O(2)(-) production from NADPH oxidase in PAEC. Increased oxidative stress from NADPH oxidase contributes to the impaired angiogenesis of PAEC in PPHN...
  11. pmc Attenuation of lipopolysaccharide-induced oxidative stress and apoptosis in fetal pulmonary artery endothelial cells by hypoxia
    Venkatesh Sampath
    Department of Pediatrics, Medical College of Wisconsin, Milwaukee, USA
    Free Radic Biol Med 46:663-71. 2009
    ..We conclude that ambient oxygen concentration modulates the severity of LPS-mediated injury in FPAEC by regulating superoxide levels produced in response to LPS...
  12. ncbi Betamethasone attenuates oxidant stress in endothelial cells from fetal lambs with persistent pulmonary hypertension
    Indira Chandrasekar
    Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53201, USA
    Pediatr Res 63:67-72. 2008
    ..Betamethasone reversed the increased superoxide/decreased cGMP levels and restored Hsp90-eNOS interactions in PPHN. Betamethasone reduces oxidative stress and improves response of pulmonary arteries to vasodilators in lambs with PPHN...
  13. pmc Inducible HSP70 regulates superoxide dismutase-2 and mitochondrial oxidative stress in the endothelial cells from developing lungs
    Adeleye J Afolayan
    Div of Neonatology, Dept of Pediatrics, Suite C460, Children s Corporate Ctr, 999 N 92nd St, Wauwatosa, WI
    Am J Physiol Lung Cell Mol Physiol 306:L351-60. 2014
    ..Our observations suggest that iHSP70 chaperones SOD-2 to the mitochondria. Impaired SOD-2-iHSP70 dissociation decreases SOD-2 import and contributes to mitochondrial oxidative stress in PPHN. ..

Research Grants30

  1. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  2. 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. ..
  3. Aldosterone impairs endothelin B-dependent synthesis of nitric oxide to promote p
    BRADLEY MARON; Fiscal Year: 2013
    ..We will use two different models of PAH in rats in vivo and LC-MS to identify ETB cysteinyl thiol oxidation product(s). These studies aim to identify novel treatment targets for PAH and other vascular diseases with similar pathobiology. ..
  4. Role of natriuretic peptides in the ductus arteriosus
    JOHN JEFFREY REESE; Fiscal Year: 2013
    ..abstract_text> ..
  5. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....