title: Role of Nitric Oxide Isoforms in Vascular and Alveolar Development and Lung Injury in Vascular Endothelial Growth Factor Overexpressing Neonatal Mice Lungs.
abstract: BACKGROUND
  The role of vascular endothelial growth factor (VEGF)-induced 3 different nitric oxide synthase (NOS) isoforms in lung development and injury in the newborn (NB) lung are not known. We hypothesized that VEGF-induced specific NOS pathways are critical regulators of lung development and injury.
  
  
  METHODS
  We studied NB wild type (WT), lung epithelial cell-targeted VEGF165 doxycycline-inducible overexpressing transgenic (VEGFTG), VEGFTG treated with a NOS1 inhibitor (L-NIO), VEGFTG x NOS2-/- and VEGFTG x NOS3+/- mice in room air (RA) for 7 postnatal (PN) days. Lung morphometry (chord length), vascular markers (Ang1, Ang2, Notch2, vWF, CD31 and VE-cadherin), cell proliferation (Ki67), vascular permeability, injury and oxidative stress markers (hemosiderin, nitrotyrosine and 8-OHdG) were evaluated.
  
  
  RESULTS
  VEGF overexpression in RA led to increased chord length and vascular markers at PN7, which were significantly decreased to control values in VEGFTG x NOS2-/- and VEGFTG x NOS3+/- lungs. However, we found no noticeable effect on chord length and vascular markers in the VEGFTG / NOS1 inhibited group. In the NB VEGFTG mouse model, we found VEGF-induced vascular permeability in the NB murine lung was partially dependent on NOS2 and NOS3-signaling pathways. In addition, the inhibition of NOS2 and NOS3 resulted in a significant decrease in VEGF-induced hemosiderin, nitrotyrosine- and 8-OHdG positive cells at PN7. NOS1 inhibition had no significant effect.
  
  
  CONCLUSIONS
  Our data showed that the complete absence of NOS2 and partial deficiency of NOS3 confers protection against VEGF-induced pathologic lung vascular and alveolar developmental changes, as well as injury markers. Inhibition of NOS1 does not have any modulating role on VEGF-induced changes in the NB lung. Overall, our data suggests that there is a significant differential regulation in the NOS-mediated effects of VEGF overexpression in the developing mouse lung.
authors.affiliation: Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8064, United States of America.
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Syed
authors.affiliation: Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8064, United States of America.
authors.forename: Rayman
authors.initials: R
authors.lastname: Choo-Wing
authors.affiliation: Department of Pathology, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06520, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.affiliation: Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8064, United States of America.
authors.forename: Vineet
authors.initials: V
authors.lastname: Bhandari
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D001808:Blood Vessels / Q000254:growth & development* / Q000378:metabolism; D005260:Female; D008168:Lung / Q000254:growth & development* / Q000378:metabolism; D055370:Lung Injury / Q000209:etiology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism* / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse