Impaired 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. In comparison with controls, fetal lung explants from eNOS -/- mice had decreased terminal lung bud formation, which was restored with rhVEGF treatment. Neonatal eNOS -/- mice were more susceptible to hyperoxia-induced inhibition of lung growth than controls, which was prevented with rhVEGF treatment. Fetal AT2 cell proliferation was increased with rhVEGF treatment only with mesenchymal cell (MC) co-culture and these effects were attenuated with anti-HGF antibody treatment. Unlike VEGF, HGF directly stimulated isolated AT2 cells even without MC co-culture. HGF directly stimulates fetal pulmonary artery endothelial cell growth and tube formation, which is attenuated by treatment with JNJ, 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-cMet signaling, and speculate that reciprocal VEGF-HGF signaling between epithelia and endothelia is disrupted in infants who develop BPD.
- Vascular endothelial growth factor, VEGF
- hepatocyte growth factor, HGF
- lung development
- endothelial nitric oxide synthase, eNOS
- bronchopulmonary dysplasia, BPD
- Copyright © 2015, American Journal of Physiology - Lung Cellular and Molecular Physiology