title: Adenovirus-mediated transfer of a minigene expressing multiple isoforms of VEGF is more effective at inducing angiogenesis than comparable vectors expressing individual VEGF cDNAs.
abstract: To assess the hypothesis that angiogenic gene therapy with the genomic form of vascular endothelial growth factor (VEGF) expressing the three major isoforms could be more potent than a vector expressing a single isoform, we designed an adenovirus vector (AdVEGF-All) expressing a VEGF cDNA/genomic hybrid gene. AdVEGF-All expressed all three major isoforms (121, 165, 189) in a 2:2:1 ratio. AdVEGF-All was 100-fold more potent than cDNA vectors expressing VEGF 121, 165, or 189 in restoring blood flow to the ischemic mouse hind limb. Interestingly, a mixture of Ad vectors individually expressing the VEGF 121, 165, and 189 cDNAs was equipotent to an equivalent dose of AdVEGF-All. Thus, a mixture of VEGF isoforms provides a more potent angiogenic response than a single isoform, suggesting that the individual isoforms function synergistically, an observation with important implications for gene and recombinant protein therapy.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Whitlock
authors.forename: Neil R
authors.initials: NR
authors.lastname: Hackett
authors.forename: Philip L
authors.initials: PL
authors.lastname: Leopold
authors.forename: Todd K
authors.initials: TK
authors.lastname: Rosengart
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D001808:Blood Vessels / Q000254:growth & development / Q000473:pathology; D002478:Cells, Cultured; D018076:DNA, Complementary; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007511:Ischemia / Q000473:pathology / Q000628:therapy*; D007866:Leg / Q000098:blood supply; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic; D020033:Protein Isoforms / Q000235:genetics; D051381:Rats; D042442:Vascular Endothelial Growth Factors / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; D020033:Protein Isoforms; D042442:Vascular Endothelial Growth Factors