Role of platelet-derived growth factor-B, vascular endothelial growth factor, insulin-like growth factor-II, mitogen-activated protein kinase and transforming growth factor-beta1 in expansion-induced lung growth in fetal sheep.
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)-beta1 induces differentiation and extracellular matrix remodelling. In the present study, we investigated the mRNA levels of PDGF-B, VEGF, IGF-II and TGF-beta1, 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-beta1 mRNA increased by 96% (P < 0.05) at 10 days TO, when bioactive TGF-beta1 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.
Wallace
Megan J
MJ
Department of Physiology, Monash University, Vic. 3800, Australia. megan.wallace@med.monash.edu.au
Thiel
Alison M
AM
Lines
Andrea M
AM
Polglase
Graeme R
GR
Sozo
Foula
F
Hooper
Stuart B
SB
D000818:Animals; D004789:Enzyme Activation; D005260:Female; D005325:Fetal Organ Maturity / Q000502:physiology*; D006133:Growth Substances / Q000502:physiology*; D017403:In Situ Hybridization; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000502:physiology; D008168:Lung / Q000196:embryology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D010766:Phosphorylation; D011247:Pregnancy; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D012756:Sheep / Q000196:embryology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology
D006133:Growth Substances; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D020928:Mitogen-Activated Protein Kinases