Vascular endothelial growth factor effect on endothelial cell proliferation, migration, and platelet-activating factor synthesis is Flk-1-dependent.
Vascular endothelial growth factor (VEGF) is a potent inducer of endothelial cell (EC) proliferation and migration in vitro as well as inflammation in vivo. We showed recently that VEGF effect on vascular permeability was dependent on the synthesis of platelet-activating factor (PAF) by EC. Consequently, we sought to evaluate by antisense knockdown of gene expression the contribution of VEGF receptors (Flt-1 and Flk-1) on these events. VEGF (10(-11) to 10(-8) M) elicited a dose-dependent increase of bovine aortic EC proliferation, migration, and PAF synthesis by up to 2.05-, 1.31- and 35.9-fold above basal levels, respectively. A treatment with two modified antisense oligomers (1-5 x 10(-7) M) directed against Flk-1 mRNA blocked by 100, 91, and 85% the proliferation, migration, and PAF synthesis mediated by VEGF, respectively. A treatment with two antisense oligomers directed against Flt-1 mRNA failed to modulate these activities. The use of placenta growth factor (up to 10(-8) M), an Flt-1-specific agonist, induced only a slight increase (0.6-fold) of PAF synthesis. These data illustrate the crucial role of Flk-1 in EC stimulation by VEGF. The capacity to inhibit the protein synthesis of Flt-1 and Flk-1 by antisense oligonucleotides provides a new approach to block VEGF pathological effects in vivo.
Bernatchez
P N
PN
Research Center, Montreal Heart Institute, Department of Pharmacology, University of Montreal, Montreal, Québec H1T 1C8, Canada.
Soker
S
S
Sirois
M G
MG
D000818:Animals; D001011:Aorta; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008222:Lymphokines / Q000494:pharmacology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation; D010972:Platelet Activating Factor / Q000096:biosynthesis*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000235:genetics* / Q000502:physiology*; D011975:Receptors, Mitogen / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor; D014158:Transcription, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D020319:Oligodeoxyribonucleotides, Antisense; D010972:Platelet Activating Factor; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D011975:Receptors, Mitogen; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1