Hepatocyte growth factor as a downstream mediator of vascular endothelial growth factor-dependent preservation of growth in the developing lung

Am J Physiol Lung Cell Mol Physiol. 2016 Jun 1;310(11):L1098-110. doi: 10.1152/ajplung.00423.2015. Epub 2016 Apr 1.


Impaired vascular endothelial growth factor (VEGF) signaling contributes to the pathogenesis of bronchopulmonary dysplasia (BPD). We hypothesized that the effects of VEGF on lung structure during development may be mediated through its downstream effects on both endothelial nitric oxide synthase (eNOS) and hepatocyte growth factor (HGF) activity, and that, in the absence of eNOS, trophic effects of VEGF would be mediated through HGF signaling. To test this hypothesis, we performed an integrative series of in vitro (fetal rat lung explants and isolated fetal alveolar and endothelial cells) and in vivo studies with normal rat pups and eNOS(-/-) mice. Compared with controls, fetal lung explants from eNOS(-/-) mice had decreased terminal lung bud formation, which was restored with recombinant human VEGF (rhVEGF) treatment. Neonatal eNOS(-/-) mice were more susceptible to hyperoxia-induced inhibition of lung growth than controls, which was prevented with rhVEGF treatment. Fetal alveolar type II (AT2) cell proliferation was increased with rhVEGF treatment only with mesenchymal cell (MC) coculture, and these effects were attenuated with anti-HGF antibody treatment. Unlike VEGF, HGF directly stimulated isolated AT2 cells even without MC coculture. HGF directly stimulates fetal pulmonary artery endothelial cell growth and tube formation, which is attenuated by treatment with JNJ-38877605, a c-Met inhibitor. rHGF treatment preserves alveolar and vascular growth after postnatal exposure to SU-5416, a VEGF receptor inhibitor. We conclude that the effects of VEGF on AT2 and endothelial cells during lung development are partly mediated through HGF-c-Met signaling and speculate that reciprocal VEGF-HGF signaling between epithelia and endothelia is disrupted in infants who develop BPD.

Keywords: bronchopulmonary dysplasia; endothelial nitric oxide synthase; hepatocyte growth factor; lung development; lung hypoplasia; nitric oxide; vascular endothelial growth factor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alveolar Epithelial Cells / physiology
  • Animals
  • Cell Adhesion
  • Cells, Cultured
  • Coculture Techniques
  • Endothelial Cells / physiology
  • Endothelium, Vascular / cytology
  • Female
  • Hepatocyte Growth Factor / physiology*
  • Lung / growth & development*
  • Lung / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide Synthase Type III / genetics
  • Pulmonary Artery / cytology
  • Pulmonary Artery / metabolism
  • Sheep
  • Vascular Endothelial Growth Factor A / physiology*


  • HGF protein, mouse
  • Vascular Endothelial Growth Factor A
  • Hepatocyte Growth Factor
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse