Role of VEGF in Perinatal Hypertension
Principal Investigator: STEVEN HERBERT ABMAN
Abstract: DESCRIPTION (provided by applicant): Advances in perinatal care, including antenatal steroids, surfactant therapy and improved ventilator strategies, have markedly increased survival of extremely low birth weight infants. However, bronchopulmonary dysplasia (BPD), the chronic lung disease that follows premature birth, remains a major cause of perinatal morbidity and mortality. BPD is a major public health problem, occurring in over 10,000 new cases per year in the USA and causing prolonged hospitalizations, recurrent respiratory exacerbations, impaired lung function into adulthood, exercise intolerance, and pulmonary hypertension in survivors. BPD is characterized by abnormal lung structure due to an arrest of vascular and alveolar growth, but mechanisms contributing to the pathogenesis and optimal treatment of BPD remain poorly understood. Vascular endothelial growth factor (VEGF) is a potent mitogen and critical survival and maintenance factor for lung vascular endothelium. VEGF and its down-stream mediator, nitric oxide (NO), are essential for lung angiogenesis during early embryogenesis, but less is known about its roles and mechanisms of its effects later during development and in the setting of neonatal lung disease. Our past studies have shown that disruption of VEGF - NO signaling causes dysmorphic lung vascular growth and decreased alveolarization in experimental and clinical BPD. Inhibition of angiogenesis impairs alveolarization during lung development, and treatment with VEGF or inhaled NO (iNO) enhances endothelial survival, vascular growth and lung structure in diverse animal models of BPD. However, randomized clinical trials have failed to demonstrate that iNO therapy consistently prevents BPD in human preterm infants, as summarized in a recent NICHD Consensus Conference. Although several issues related to patient selection and study design may account for variability between studies, the failure of iNO therapy to consistently prevent BPD further highlights the importance of developing alternate strategies to preserve endothelial function and angiogenesis in premature infants. Since VEGF treatment improves vascular and alveolar growth in experimental BPD yet has no direct effects on airway epithelium, we hypothesize that in addition to NO activation, VEGF-induced enhancement of lung structure may be mediated through non-NO dependent pathways, and that these pathways may mediate critical epithelial-mesenchymal interactions that are essential for improving lung vascular and alveolar growth in BPD. Based on strong preliminary data, we further hypothesize that the effects of VEGF on lung structure are dependent upon stimulation of hepatocyte growth factor and enhanced retinoic acid production by vascular endothelium ("angiocrine factors"). In this renewal, we propose a series of integrative studies that incorporate physiologic, cell and molecular approaches towards understanding BPD.
Funding Period: 2001-06-20 - 2016-07-31
more information: NIH RePORT
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Department of Medicine, Cardiovascular Pulmonary Research Section, University of Colorado Health Sciences Center, 4200 E 9th Ave, Denver, CO 80262, USA
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Pediatric Heart Lung Center, Dept of Pediatrics, Univ of Colorado Health Sciences Center, P15 4460A, Mail Stop 8614, 12700 East 19th Ave, Aurora, CO 80045, USA
Am J Physiol Lung Cell Mol Physiol 302:L36-46. 2012..We speculate that impaired VEGF signaling in utero due to exposure of high amniotic fluid levels of sFlt-1 in PE disrupts lung growth and contributes to the increased risk of BPD in infants born to mothers with PE...
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Paediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, CO 80045, USA
Eur Respir J 40:1516-22. 2012..Circulating vascular progenitor cells are decreased in the cord blood of preterm infants who develop moderate and severe BPD. These findings suggest that prenatal factors contribute to late respiratory outcomes in preterm infants...
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Department of Neonatology, University of Colorado School of Medicine, Aurora, Colorado, USA
Pediatr Res 73:252-62. 2013..Endothelin-1 (ET-1) and Rho-kinase (ROCK) increase vascular tone in experimental persistent pulmonary hypertension of the newborn (PPHN). Whether ET-1 activates ROCK to decrease angiogenesis in the developing lung remains unknown...
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Department of Pediatrics, Pediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, CO 80045, USA
J Immunol 190:2913-23. 2013....
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Pediatric Heart Lung Center, Section of Neonatology, University of Colorado Denver, Aurora, CO 80045, USA
Am J Physiol Lung Cell Mol Physiol 304:L894-901. 2013..We concluded that increased 5-HT contributes to high PVR in experimental PPHN through activation of the 5-HT2A receptor and that SSRI infusion further increases PVR in this model...
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Department of Pediatrics, Section of Critical Care, Pediatric Heart Lung Center, University of Colorado, School of Medicine, Aurora, Colorado 80045, USA
Curr Opin Pediatr 25:329-37. 2013....
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Pediatric Heart Lung Center, University of Colorado School of Medicine, Mail Stop 8614, 12700 E 19th Ave, Aurora, CO 80045, USA
Am J Physiol Lung Cell Mol Physiol 305:L73-81. 2013..During oxidative stress, preterm ECFC-CM, but not term ECFC-CM, loses its benefit. The inability of term ECFC-CM to promote alveolarization may limit its therapeutic potential. ..
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Pediatric Heart Lung Center, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA
J Pediatr 163:905-7. 2013..Unlike newborns who develop bronchopulmonary dysplasia, those with congenital diaphragmatic hernia had increased and highly-proliferative cord blood ECFCs. ..
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1 Department of Pathology
Ann Am Thorac Soc 10:474-81. 2013....
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Department of Pathology and Laboratory Medicine, University of Colorado School of Medicine and Children s Hospital Colorado, Aurora, CO Pediatric Heart Lung Center, University of Colorado School of Medicine and Children s Hospital Colorado, Aurora, CO
J Pediatr 164:192-5. 2014..Using 3-dimensional reconstruction of ACD/MPV lung tissue, we report that the veins in MPV are intrapulmonary shunt vessels, and speculate that MPV contributes to the poor prognosis. ..
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Univ of Colorado School of Medicine, 12631 E 17th Ave, C302, Aurora, CO 80045
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Perinatal Research Facility, 13243 E 23rd Ave, Mail Stop F441, Aurora, CO 80045
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Perinatal Research Facility, 13243 E 23rd Ave, Mail Stop F441, Aurora, CO 80045
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Division of Neonatology, Department of Pediatrics, Weill Cornell Medical College, New York, NY Electronic address
J Pediatr 164:744-8. 2014..To assess whether the combination of early inhaled nitric oxide (iNO) therapy and vitamin A supplementation lowers the incidence of bronchopulmonary dysplasia (BPD) in premature newborns with respiratory failure...
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Pediatric Heart Lung Center, Aurora, CO, USA
Am J Physiol Lung Cell Mol Physiol 301:L937-44. 2011..We speculate that prolonged exposure to SSRIs can induce PPHN through direct effects on the fetal pulmonary circulation...
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Division of Neonatology, Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, USA
Am J Physiol Lung Cell Mol Physiol 301:L860-71. 2011..We conclude that fetuses with IUGR are characterized by decreased alveolar and vascular growth and PAEC dysfunction in vitro. This may contribute to the increased risk for adverse respiratory outcomes and BPD in infants with IUGR...
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Pediatric Heart Lung Center, Sections of Neonatology and Pulmonary Medicine, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
Am J Physiol Lung Cell Mol Physiol 301:L755-64. 2011..We speculate that increased NO-insensitive sGC may contribute to the pathogenesis of PPHN, and cinaciguat may provide a novel treatment of severe pulmonary hypertension...
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Department of Pediatrics, Pediatric Heart Lung Center, University of Colorado School of Medicine, Denver, Colo, USA
Biol Neonate 90:135-44. 2006..We speculate that BAY 41-2272 may provide a new therapy for chronic PH...
- Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung diseaseBernard Thebaud
Department of Pediatrics, Division of Neonatology, Vascular Biology Group, University of Alberta, HMRC 407, Edmonton, AB, T6G 2S2, Canada
Am J Respir Crit Care Med 175:978-85. 2007....
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Section of Neonatology, Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, USA
Am J Respir Crit Care Med 176:1146-53. 2007..Mechanisms that impair angiogenesis in neonatal persistent pulmonary hypertension (PPHN) are poorly understood...
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Pediatric Heart Lung Center, Dept of Pediatrics, Univ of Colorado Health Sciences Center, Mail Stop 8317, 12800 E 19th Ave, PO Box 6511, Aurora, CO 80045, USA
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Pediatric Heart Lung Center, Dept of Pediatrics, Univ of Colorado School of Medicine and The Children s Hospital, Mail Stop 8317, PO Box 6511, Aurora, CO 80045 USA
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Department of Pediatrics, University of Colorado School of Medicine, Denver, CO, USA
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The Pediatric Heart Lung Center, Sections of Neonatology and Pulmonary Medicine, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
Am J Physiol Heart Circ Physiol 295:H1505-13. 2008..001). We conclude that high ROCK activity opposes pulmonary vasodilation in utero and that the myogenic response maintains high PVR in the normal fetal lung through ROCK activation...
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Pediatric Heart Lung Center, University of Colorado School of Medicine and The Children s Hospital, Aurora, Colorado 80045, USA
Annu Rev Med 60:13-23. 2009..This article briefly reviews preclinical data and the current status of ETRAs in the clinical management of PAH...
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Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine, Aurora, 80045, USA
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Pediatric Heart Lung Center, University of Colorado, Denver School of Medicine, Aurora, CO 80045, USA
Am J Respir Crit Care Med 180:454-61. 2009..Endothelial progenitor cells, such as self-renewing highly proliferative endothelial colony-forming cells (ECFCs), may participate in vascular repair. The effect of hyperoxia on ECFC growth is unknown...
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Pediatric Heart Lung Center Univ of Colorado Denver School of Medicine, Aurora, CO 80045, USA
Am J Physiol Lung Cell Mol Physiol 297:L1160-9. 2009..NO treatment also increases growth during hyperoxia. Exogenous VEGF or NO may protect preterm ECFCs from the adverse effects of hyperoxia and preservation of ECFC function may improve outcomes of preterm infants...
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Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado Denver, 12800 E 19th Ave, Aurora, CO 80045, USA
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Dept of Pediatrics, Univ of Colorado Health Sciences Center, Aurora, CO 80045, USA
Am J Physiol Lung Cell Mol Physiol 299:L735-48. 2010..Moreover, moderate postnatal hyperoxia after antenatal ETX restores lung growth and prevents pulmonary hypertension during infancy...
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Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine and Children s Hospital, Aurora, Colorado, USA
Curr Opin Pediatr 23:298-304. 2011..Advances in pulmonary vascular biology over the past few decades have significantly expanded therapeutic strategies; however, many unique issues persist regarding our understanding of pediatric PAH...
- Vitamin D treatment improves survival and infant lung structure after intra-amniotic endotoxin exposure in rats: potential role for the prevention of bronchopulmonary dysplasiaErica Mandell
Dept of Pediatrics, The Children s Hospital, B395, 13123 East 16th Ave, Aurora, CO 80045
Am J Physiol Lung Cell Mol Physiol 306:L420-8. 2014..We conclude that antenatal vit D therapy improved oxygenation and survival in newborn rat pups and enhanced late lung structure after exposure to IA ETX in vivo, which may partly be due to direct effects on vascular and alveolar growth...
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