bFGF and VEGF synergistically enhance endothelial cytoprotection via decay-accelerating factor induction.
The complement-regulatory protein decay-accelerating factor (DAF) can be upregulated on endothelial cells (EC) by protein kinase C (PKC)-dependent and -independent pathways. We hypothesized that basic fibroblast growth factor (bFGF) might induce EC DAF expression, providing a cytoprotective mechanism for angiogenic neovessels against complement-mediated injury. Incubation of umbilical vein, aortic, and dermal EC with bFGF or vascular endothelial growth factor (VEGF) significantly increased DAF expression. Growth factor-induced EC proliferation was inhibited by PKC antagonists. In contrast, although PKC antagonists inhibited VEGF-induced DAF expression, bFGF-induced DAF was unaffected. Investigation of mitogen-activated kinase (MAPK) pathways also revealed differences, with bFGF-induced DAF dependent on p44/42 and p38 MAPK and VEGF requiring activation of p38 MAPK alone. Upregulation of DAF by bFGF was functionally relevant, reducing C3 deposition on EC after complement activation by 60% and resulting in marked reduction in complement-mediated EC lysis. bFGF and VEGF were synergistic in terms of DAF expression, resulting in enhanced cytoprotection. These observations reveal parallel PKC-dependent and -independent pathways regulating complement activation during angiogenesis. Further elucidation of these pathways may provide important insights into innate cytoprotective mechanisms in endothelium.
Mason
Justin C
JC
British Heart Foundation Cardiovascular Medicine Unit, National Heart and Lung Institute, Imperial College School of Science, Technology and Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, United Kingdom. justin.mason@ic.ac.uk
Lidington
Elaine A
EA
Ahmad
Saifur R
SR
Haskard
Dorian O
DO
D015703:Antigens, CD / Q000378:metabolism; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism*; D018957:CD59 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D003176:Complement C3 / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D019610:Cytoprotection; D004357:Drug Synergism; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D008222:Lymphokines / Q000494:pharmacology*; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D015703:Antigens, CD; C497857:CD46 protein, human; D018958:CD55 Antigens; D018957:CD59 Antigens; D003176:Complement C3; D003169:Complement Inactivator Proteins; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008222:Lymphokines; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D011500:Protein Synthesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D003513:Cycloheximide; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases