Basic fibroblast growth factor-stimulated endothelial cell movement is mediated by a pertussis toxin-sensitive pathway regulating phospholipase A2 activity.
Basic fibroblast growth factor (bFGF) stimulates migration and proliferation of vascular endothelial cells (EC). Fibroblast growth factor (FGF) receptors have an intrinsic tyrosine kinase activity involved in FGF-mediated proliferation, but the signal transduction pathway(s) responsible for movement is not known. We compared the role of signal-transducing G-proteins in migratory and proliferative responses of bovine aortic EC in vitro. Pertussis toxin, which ADP-ribosylates susceptible G-proteins, reduced bFGF-stimulated EC migration by 80%. The toxin did not block serum-stimulated movement, indicating that structural components required for motility were not impaired. The toxin did not inhibit bFGF-stimulated EC proliferation, showing that distinct intracellular signaling mechanisms are involved in the migratory and proliferative responses to bFGF. Three experimental approaches indicated that promigratory responses were due to release of arachidonic acid: (i) of the second messengers induced by G-protein-coupled effectors, only arachidonic acid over-came the pertussis toxin block, (ii) bFGF stimulated arachidonic acid release from EC in a pertussis toxin-sensitive manner, and (iii) phospholipase A2 inhibitors blocked the EC migration in response to bFGF. These data provide evidence that the migratory response of vascular EC to bFGF may be mediated by a G-protein-coupled phospholipase A2 activity.
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Department of Cell Biology, Cleveland Clinic Research Institute, Ohio 44195.
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D000818:Animals; D001011:Aorta; D016718:Arachidonic Acid / Q000378:metabolism; D034341:Aristolochic Acids; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D007700:Kinetics; D037342:Pertussis Toxin; D010616:Phenanthrenes / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D015290:Second Messenger Systems / Q000187:drug effects; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D034341:Aristolochic Acids; D010616:Phenanthrenes; D010566:Virulence Factors, Bordetella; D016222:Fibroblast Growth Factor 2; D016718:Arachidonic Acid; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D004247:DNA; D002772:Cholera Toxin; C000228:aristolochic acid I; D037342:Pertussis Toxin; D010741:Phospholipases A; D054467:Phospholipases A2; D019204:GTP-Binding Proteins