Blockade of in vivo VEGF-mediated angiogenesis by antisense gene therapy: role of Flk-1 and Flt-1 receptors.
Angiogenesis, the formation of new blood vessels from preexisting ones, is a critical component of various pathologies such as tumor progression, rheumatoid arthritis, and retinopathies. Vascular endothelial growth factor (VEGF) is a mitogenic and chimiotactic factor capable of inducing angiogenesis through the activation of its receptors, fetal liver kinase-1 (Flk-1) and fms-like tyrosine kinase-1 (Flt-1), expressed on endothelial cells. The purpose of the present study was to assess if a treatment with antisense (AS) oligonucleotides directed against VEGF receptors Flk-1 or Flt-1 mRNA could prevent VEGF-mediated angiogenesis. With the use of miniosmotic pumps, phosphate-buffered saline, VEGF, or VEGF combined with AS-Flk-1, AS-Flt-1, or AS-scrambled oligonucleotides were released in mouse testis for 14 days. VEGF (1, 2.5, and 5 microg) increased the formation of new capillary blood vessels by 236, 246, and 287%, respectively. The combination of AS-Flk-1 or AS-Flt-1 (200 microg) to VEGF (2.5 microg) reduced by 87 and 85% the formation of new blood vessels, respectively, and the expression of their corresponding proteins. These data demonstrate the therapeutical potential of AS-Flk-1 or AS-Flt-1 to prevent VEGF-mediated angiogenesis in vivo.
Marchand
Geneviève S
GS
Montreal Heart Institute, 5000 Belanger St., Montreal, Quebec, Canada H1T 1C8.
Noiseux
Nicolas
N
Tanguay
Jean-François
JF
Sirois
Martin G
MG
D000818:Animals; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D015316:Genetic Therapy; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics*; D017978:Receptors, Growth Factor / Q000187:drug effects / Q000235:genetics*; D040262:Receptors, Vascular Endothelial Growth Factor; D013997:Time Factors; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; 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