title: Lack of EC-SOD worsens alveolar and vascular development in a neonatal mouse model of bleomycin-induced bronchopulmonary dysplasia and pulmonary hypertension.
abstract: BACKGROUND
  Pulmonary hypertension (PH) worsens clinical outcomes in former preterm infants with bronchopulmonary dysplasia (BPD). Oxidant stress disrupts alveolar and vascular development in models of BPD. Bleomycin causes oxidative stress and induces BPD and PAH in neonatal rats. Disruption in the vascular endothelial growth factor (VEGF) and nitric oxide signaling pathways contributes to BPD. We hypothesized that loss of EC-SOD would worsen PAH associated with BPD in a neonatal mouse model of bleomycin-induced BPD by disrupting the VEGF/NO signaling pathway.
  
  
  METHODS
  Neonatal wild-type mice (WT), and mice lacking EC-SOD (EC-SOD KO) received intraperitoneal bleomycin (2 units/kg) or phosphate-buffered saline (PBS) three times weekly and were evaluated at weeks 3 or 4.
  
  
  RESULTS
  Lack of EC-SOD impaired alveolar development and resulted in PH (elevated right ventricular systolic pressures, right ventricular hypertrophy (RVH)), decreased vessel density, and increased small vessel muscularization. Exposure to bleomycin further impaired alveolar development, worsened RVH and vascular remodeling. Lack of EC-SOD and bleomycin treatment decreased lung total and phosphorylated VEGFR2 and eNOS protein expression.
  
  
  CONCLUSIONS
  EC-SOD is critical in preserving normal lung development and loss of EC-SOD results in disrupted alveolar development, PAH and vascular remodeling at baseline, which is further worsened with bleomycin and associated with decreased activation of VEGFR2.
authors: Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado.
authors: Cassidy
authors: C
authors: Delaney
authors: Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado.
authors: Rachel H
authors: RH
authors: Wright
authors: Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado.
authors: Jen-Ruey
authors: JR
authors: Tang
authors: Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado.
authors: Crystal
authors: C
authors: Woods
authors: Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado.
authors: Leah
authors: L
authors: Villegas
authors: Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado.
authors: Laurie
authors: L
authors: Sherlock
authors: Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.
authors: Rashmin C
authors: RC
authors: Savani
authors: Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado.
authors: Steven H
authors: SH
authors: Abman
authors: Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado.
authors: Eva
authors: E
authors: Nozik-Grayck
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001761:Bleomycin; D001997:Bronchopulmonary Dysplasia / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress; D010641:Phenotype; D010766:Phosphorylation; D011650:Pulmonary Alveoli / Q000098:blood supply* / Q000201:enzymology* / Q000473:pathology; D011651:Pulmonary Artery / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D066253:Vascular Remodeling; D018497:Ventricular Dysfunction, Right / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D016278:Ventricular Function, Right; D017725:Ventricular Pressure
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D001761:Bleomycin; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D013482:Superoxide Dismutase; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2