title: Critical role of the axonal guidance cue EphrinB2 in lung growth, angiogenesis, and repair.
abstract: BACKGROUND
  Lung diseases characterized by alveolar damage currently lack efficient treatments. The mechanisms contributing to normal and impaired alveolar growth and repair are incompletely understood. Axonal guidance cues (AGC) are molecules that guide the outgrowth of axons to their targets. Among these AGCs, members of the Ephrin family also promote angiogenesis, cell migration, and organogenesis outside the nervous system. The role of Ephrins during alveolar growth and repair is unknown.
  
  
  OBJECTIVE
  We hypothesized that EphrinB2 promotes alveolar development and repair.
  
  
  METHODS
  We used in vitro and in vivo manipulation of EphrinB2 signaling to assess the role of this AGC during normal and impaired lung development.
  
  
  RESULTS
  In vivo EphrinB2 knockdown using intranasal siRNA during the postnatal stage of alveolar development in rats arrested alveolar and vascular growth. In a model of O(2)-induced arrested alveolar growth in newborn rats, air space enlargement, loss of lung capillaries, and pulmonary hypertension were associated with decreased lung EphrinB2 and receptor EphB4 expression. In vitro, EphrinB2 preserved alveolar epithelial cell viability in O(2), decreased O(2)-induced alveolar epithelial cell apoptosis, and accelerated alveolar epithelial cell wound healing, maintained lung microvascular endothelial cell viability, and proliferation and vascular network formation. In vivo, treatment with intranasal EphrinB2 decreased alveolar epithelial and endothelial cell apoptosis, preserved alveolar and vascular growth in hyperoxic rats, and attenuated pulmonary hypertension.
  
  
  CONCLUSIONS
  The AGC EphrinB2 may be a new therapeutic target for lung repair and pulmonary hypertension.
authors.affiliation: Department of Pediatrics, School of Human Development, Women and Children’s Health Research Institute, Edmonton, Canada.
authors.forename: Arul
authors.initials: A
authors.lastname: Vadivel
authors.forename: Tim
authors.initials: T
authors.lastname: van Haaften
authors.forename: Rajesh S
authors.initials: RS
authors.lastname: Alphonse
authors.forename: Gloria-Juliana
authors.initials: GJ
authors.lastname: Rey-Parra
authors.forename: Lavinia
authors.initials: L
authors.lastname: Ionescu
authors.forename: Al
authors.initials: A
authors.lastname: Haromy
authors.forename: Farah
authors.initials: F
authors.lastname: Eaton
authors.forename: Evangelos
authors.initials: E
authors.lastname: Michelakis
authors.forename: Bernard
authors.initials: B
authors.lastname: Thébaud
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004727:Endothelium / Q000502:physiology; D036388:Ephrin-B2 / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006976:Hypertension, Pulmonary / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000254:growth & development*; D055370:Lung Injury / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000254:growth & development; D051381:Rats; D036081:Receptors, Eph Family / Q000502:physiology; D014945:Wound Healing / Q000502:physiology
chemical_list: D036388:Ephrin-B2; D036081:Receptors, Eph Family