Ephrin-B2 reverse signaling increases α5β1 integrin-mediated fibronectin deposition and reduces distal lung compliance

Katherine M. Bennett, Maria D. Afanador, Charitharth V. Lal, Haiming Xu, Elizabeth Persad, Susan K. Legan, George Chenaux, Michael Dellinger, Rashmin C. Savani, Christopher Dravis, Mark Henkemeyer, Margaret A. Schwarz

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Alveolar growth abnormalities and severe respiratory dysfunction are often fatal. Identifying mechanisms that control epithelial proliferation and enlarged, poorly septated airspaces is essential in developing new therapies for lung disease. The membrane-bound ligand ephrin-B2 is strongly expressed in lung epithelium, and yet in contrast to its known requirement for arteriogenesis, considerably less isknownregarding the function of this protein in the epithelium. We hypothesize that the vascular mediator ephrin-B2 governs alveolar growth and mechanics beyond the confines of the endothelium. We used the in vivo manipulation of ephrin-B2 reverse signaling to determine the role of this vascularmediator in thepulmonary epithelium and distal lung mechanics. We determined that the ephrin-B2 gene (EfnB2) is strongly expressed in alveolar Type 2 cells throughout development and into adulthood. The role of ephrin-B2 reverse signaling in the lung was assessed in Efnb2LacZ/6YFDV mutants that coexpress the intracellular truncated ephrin-B2-β-galactosidase fusion and an intracellular point mutant ephrin-B2 protein that is unable to become tyrosine-phosphorylated or to interact with either the SH2 or PDZ domain-containing downstream signaling proteins. In these viable mice, we observed pulmonary hypoplasia and altered pulmonary mechanics, as evidenced by a marked reduction in lung compliance. Associated with the reduction in lung compliance was a significant increase in insoluble fibronectin (FN) basement membrane matrix assembly with FN deposition, and a corresponding increase in the α5 integrin receptor required for FN fibrillogenesis. These experiments indicate that ephrin-B2 reverse signaling mediates distal alveolar formation, fibrillogenesis, and pulmonary compliance.

Original languageEnglish (US)
Pages (from-to)680-687
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Issue number4
StatePublished - Oct 2013


  • Alveoli
  • Arterial
  • Fibronectin
  • Pulmonary mechanics
  • α5β1 integrin

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology


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