title: Gene transfer using the mature form of VEGF-D reduces neointimal thickening through nitric oxide-dependent mechanism.
abstract: Gene transfer to the vessel wall using vascular endothelial growth factors (VEGFs) has shown therapeutic potential for the treatment of restenosis. In this study, we evaluated the effect of catheter-mediated adenoviral (Ad) gene transfer of the mature form of VEGF-D (VEGF-D(DeltaNDeltaC)) in balloon-denuded cholesterol-fed rabbit aorta. AdLacZ was used as a control. Transduced VEGF-D(DeltaNDeltaC) mRNA was detectable in the arterial wall with RT-PCR at 6, 14 and 28 days. Gene transfer efficiency as detected with X-gal staining 6 days after the AdLacZ transduction was 1.91 +/- 1.32% in intima. AdVEGF-D(DeltaNDeltaC) gene transfer led to 52% reduction in intima/media ratio (I/M) as compared to the AdLacZ controls at 14 days time point. At 6 days there were no differences in I/M, but the number of macrophages in the vessel wall was 85% lower in the AdVEGF-D(DeltaNDeltaC) group as compared to the controls. The therapeutic effect was no longer detectable 28 days after the gene transfer. The therapeutic effect of VEGF-D(DeltaNDeltaC) was nitric oxide (NO)-dependent as the feeding of NO synthase inhibitor, L-NAME, blocked the reduction in intimal thickening. It is concluded that AdVEGF-D(DeltaNDeltaC) gene transfer reduces intimal thickening and macrophage influx into the vessel wall in balloon-denuded rabbit aortas.
authors.affiliation: Department of Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Rutanen
authors.forename: A-M
authors.initials: AM
authors.lastname: Turunen
authors.forename: M
authors.initials: M
authors.lastname: Teittinen
authors.forename: T T
authors.initials: TT
authors.lastname: Rissanen
authors.forename: T
authors.initials: T
authors.lastname: Heikura
authors.forename: J K
authors.initials: JK
authors.lastname: Koponen
authors.forename: M
authors.initials: M
authors.lastname: Gruchala
authors.forename: M
authors.initials: M
authors.lastname: Inkala
authors.forename: S
authors.initials: S
authors.lastname: Jauhiainen
authors.forename: M O
authors.initials: MO
authors.lastname: Hiltunen
authors.forename: M P
authors.initials: MP
authors.lastname: Turunen
authors.forename: S A
authors.initials: SA
authors.lastname: Stacker
authors.forename: M G
authors.initials: MG
authors.lastname: Achen
authors.forename: S
authors.initials: S
authors.lastname: Ylä-Herttuala
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001011:Aorta; D001018:Aortic Diseases / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002404:Catheterization; D003251:Constriction, Pathologic / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000378:metabolism; D011817:Rabbits; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic / Q000379:methods*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics* / Q000378:metabolism
chemical_list: D042643:Vascular Endothelial Growth Factor D; D009569:Nitric Oxide