Intravascular adenovirus-mediated VEGF-C gene transfer reduces neointima formation in balloon-denuded rabbit aorta.
BACKGROUND
Gene transfer to the vessel wall may provide new possibilities for the treatment of vascular disorders, such as postangioplasty restenosis. In this study, we analyzed the effects of adenovirus-mediated vascular endothelial growth factor (VEGF)-C gene transfer on neointima formation after endothelial denudation in rabbits. For comparison, a second group was treated with VEGF-A adenovirus and a third group with lacZ adenovirus. Clinical-grade adenoviruses were used for the study.


RESULTS
Aortas of cholesterol-fed New Zealand White rabbits were balloon-denuded, and gene transfer was performed 3 days later. Animals were euthanized 2 and 4 weeks after the gene transfer, and intima/media ratio (I/M), histology, and cell proliferation were analyzed. Two weeks after the gene transfer, I/M in the lacZ-transfected control group was 0. 57+/-0.04. VEGF-C gene transfer reduced I/M to 0.38+/-0.02 (P:<0.05 versus lacZ group). I/M in VEGF-A-treated animals was 0.49+/-0.17 (P:=NS). The tendency that both VEGF groups had smaller I/M persisted at the 4-week time point, when the lacZ group had an I/M of 0.73+/-0.16, the VEGF-C group 0.44+/-0.14, and the VEGF-A group 0. 63+/-0.21 (P:=NS). Expression of VEGF receptors 1, 2, and 3 was detected in the vessel wall by immunocytochemistry and in situ hybridization. As an additional control, the effect of adenovirus on cell proliferation was analyzed by performing gene transfer to intact aorta without endothelial denudation. No differences were seen in smooth muscle cell proliferation or I/M between lacZ adenovirus and 0.9% saline-treated animals.


CONCLUSIONS
Adenovirus-mediated VEGF-C gene transfer may be useful for the treatment of postangioplasty restenosis and vessel wall thickening after vascular manipulations.
Hiltunen
M O
MO
A.I. Virtanen Institute, University of Kuopio, Kuopio, Finland.
Laitinen
M
M
Turunen
M P
MP
Jeltsch
M
M
Hartikainen
J
J
Rissanen
T T
TT
Laukkanen
J
J
Niemi
M
M
Kossila
M
M
Häkkinen
T P
TP
Kivelä
A
A
Enholm
B
B
Mansukoski
H
H
Turunen
A M
AM
Alitalo
K
K
Ylä-Herttuala
S
S
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D001024:Aortic Valve Stenosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018014:Gene Transfer Techniques; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D011817:Rabbits; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D017978:Receptors, Growth Factor / Q000096:biosynthesis; D040262:Receptors, Vascular Endothelial Growth Factor; D014162:Transfection; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D040281:Vascular Endothelial Growth Factor Receptor-1; D040321:Vascular Endothelial Growth Factor Receptor-3
D016228:Endothelial Growth Factors; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040321:Vascular Endothelial Growth Factor Receptor-3