A - Human Necessities – 61 – K
Patent
A - Human Necessities
61
K
A61K 48/00 (2006.01) A61K 31/70 (2006.01) A61K 38/17 (2006.01) A61K 38/18 (2006.01) C12N 15/11 (2006.01) A61K 38/00 (2006.01)
Patent
CA 2268379
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 - 10-8M) 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 (10-7- 5x10-7M) directed against Ftk-1 mRNA blocked by 100%, 91% and 85% the migration, proliferation 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 (10-8M), a Flt-1- specific agonist, induced only a slight increase (0.6-fold) of PAF synthesis. These data illustrate the crucial role of Flk-1 upon 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. Antagonists of VEGF receptors, particularly the Flk-1 receptor, are contemplated as tools equivalent to the antisense molecules for their anti-angiogenic effect.
Fonds de Recherche de L'institut de Cardiologie
Goudreau Gage Dubuc
Sirois Martin G.
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