Role of platelet-derived growth factor-B, vascular endothelial growth factor, insulin-like growth factor-II, mitogen-activated protein kinase and transforming growth factor-β1 in expansion-induced lung growth in fetal sheep
Megan J. Wallace A B , Alison M. Thiel A , Andrea M. Lines A , Graeme R. Polglase A , Foula Sozo A and Stuart B. Hooper A
+ Author Affiliations
- Author Affiliations
A Department of Physiology, Monash University, Vic. 3800, Australia.
B Corresponding author. Email: megan.wallace@med.monash.edu.au
Reproduction, Fertility and Development 18(6) 655-665 https://doi.org/10.1071/RD05163
Submitted: 13 December 2005 Accepted: 21 March 2006 Published: 22 June 2006
Abstract
Increased fetal lung expansion induces lung growth, cell differentiation and extracellular matrix remodelling, although the mechanisms involved are unknown. Platelet-derived growth factor (PDGF)-B, vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF)-II are mitogens activating the mitogen-activated protein kinase (MAPK) pathway, whereas transforming growth factor (TGF)-β1 induces differentiation and extracellular matrix remodelling. In the present study, we investigated the mRNA levels of PDGF-B, VEGF, IGF-II and TGF-β1, as well as active MAPK levels, during increased fetal lung expansion induced by tracheal obstruction (TO) in sheep for 0 (controls), 36 h or 2, 4, or 10 days (n = 5 in each group). The 3.7-kb VEGF transcript increased by 30% (P < 0.05) at 36 h TO. The expression of PDGF-B decreased by approximately 25% (P < 0.01) at 2–10 days TO. In contrast, TGF-β1 mRNA increased by 96% (P < 0.05) at 10 days TO, when bioactive TGF-β1 decreased by 55% (P < 0.05). Insulin-like growth factor-II mRNA tended to increase at 10 days TO (37% above controls; P = 0.07), whereas mRNA for its receptor, IGF1R, was reduced by TO. There was no change in active MAPK levels preceding or at the time of a TO-induced 800% increase in cell proliferation. We conclude that VEGF is likely to promote expansion-induced endothelial cell proliferation, but the mechanisms underlying expansion-induced proliferation of fibroblasts and alveolar epithelial cells are unlikely to be mediated by increases in PDGF-B or IGF-II expression or activation of the MAPK pathway.
Extra keywords: fetal lung development, fetal lung growth, growth factors, tracheal obstruction.
Acknowledgments
The authors are indebted to Alex Satragno for his assistance with the surgical preparation of animals and to Valerie Zahra and Caitlin Filby for assistance in the laboratory. The authors thank Chris Woodall (Department of Veterinary Pathology, University of Edinburgh, UK) for the gift of the TGF-β1 and PDGF-B cDNA probes. The experiments described in the present study were funded by the National Health and Medical Research Council of Australia (NH&MRC).
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