title: Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization.
abstract: BACKGROUND
  Bronchopulmonary dysplasia (BPD) and pulmonary emphysema, both significant global health problems, are characterized by a loss of alveoli. Vascular endothelial growth factor (VEGF) is a trophic factor required for endothelial cell survival and is abundantly expressed in the lung.
  
  
  RESULTS
  We report that VEGF blockade decreases lung VEGF and VEGF receptor 2 (VEGFR-2) expression in newborn rats and impairs alveolar development, leading to alveolar simplification and loss of lung capillaries, mimicking BPD. In hyperoxia-induced BPD in newborn rats, air space enlargement and loss of lung capillaries are associated with decreased lung VEGF and VEGFR-2 expression. Postnatal intratracheal adenovirus-mediated VEGF gene therapy improves survival, promotes lung capillary formation, and preserves alveolar development in this model of irreversible lung injury. Combined VEGF and angiopoietin-1 gene transfer matures the new vasculature, reducing the vascular leakage seen in VEGF-induced capillaries.
  
  
  CONCLUSIONS
  These findings underscore the importance of the vasculature in what is traditionally thought of as an airway disease and open new therapeutic avenues for lung diseases characterized by irreversible loss of alveoli through the modulation of angiogenic growth factors.
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Alberta, Edmonton, Canada. bthebaud@ualberta.ca
authors.forename: Bernard
authors.initials: B
authors.lastname: Thébaud
authors.forename: Faruqa
authors.initials: F
authors.lastname: Ladha
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
authors.forename: Monika
authors.initials: M
authors.lastname: Sawicka
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.forename: Farah
authors.initials: F
authors.lastname: Eaton
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Gwyneth
authors.initials: G
authors.lastname: Harry
authors.forename: Alois
authors.initials: A
authors.lastname: Haromy
authors.forename: Greg
authors.initials: G
authors.lastname: Korbutt
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
mesh_terms: D000256:Adenoviridae; D000792:Angiography; D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000628:therapy*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology / Q000648:ultrastructure; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D018496:Hyperoxia / Q000628:therapy*; D007231:Infant, Newborn; D008168:Lung / Q000098:blood supply*; D055370:Lung Injury; D018919:Neovascularization, Physiologic; D011650:Pulmonary Alveoli / Q000098:blood supply*; D011651:Pulmonary Artery; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000627:therapeutic use*
chemical_list: D042461:Vascular Endothelial Growth Factor A