Local gene transfer of phVEGF-2 plasmid by gene-eluting stents: an alternative strategy for inhibition of restenosis.
BACKGROUND
Drug-eluting stents represent a useful strategy for the prevention of restenosis using various antiproliferative drugs. These strategies share the liability of impairing endothelial recovery, thereby altering the natural biology of the vessel wall and increasing the associated risk of stent thrombosis. Accordingly, we tested the hypothesis that local delivery via gene-eluting stent of naked plasmid DNA encoding for human vascular endothelial growth factor (VEGF)-2 could achieve similar reductions in neointima formation while accelerating, rather than inhibiting, reendothelialization.


RESULTS
phVEGF 2-plasmid (100 or 200 microg per stent)-coated BiodivYsio phosphorylcholine polymer stents versus uncoated stents were deployed in a randomized, blinded fashion in iliac arteries of 40 normocholesterolemic and 16 hypercholesterolemic rabbits. Reendothelialization was nearly complete in the VEGF stent group after 10 days and was significantly greater than in control stents (98.7+/-1% versus 79.0+/-6%, P<0.01). At 3 months, intravascular ultrasound analysis revealed that lumen cross-sectional area (4.2+/-0.4 versus 2.27+/-0.3 mm(2), P<0.001) was significantly greater and percent cross-sectional narrowing was significantly lower (23.4+/-6 versus 51.2+/-10, P<0.001) in VEGF stents compared with control stents implanted in hypercholesterolemic rabbits. Transgene expression was detectable in the vessel wall along with improved functional recovery of stented segments, resulting in a 2.4-fold increase in NO production.


CONCLUSIONS
Acceleration of reendothelialization via VEGF-2 gene-eluting stents provides an alternative treatment strategy for the prevention of restenosis. VEGF-2 gene-eluting stents may be considered as a stand-alone or combination therapy.
Walter
Dirk H
DH
Department of Medicine, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass 02135, USA.
Cejna
Manfred
M
Diaz-Sandoval
Larry
L
Willis
Sean
S
Kirkwood
Laura
L
Stratford
Peter W
PW
Tietz
Anne B
AB
Kirchmair
Rudolf
R
Silver
Marcy
M
Curry
Cindy
C
Wecker
Andrea
A
Yoon
Young-Sup
YS
Heidenreich
Regina
R
Hanley
Allison
A
Kearney
Marianne
M
Tio
Fermin O
FO
Kuenzler
Patrik
P
Isner
Jeffrey M
JM
Losordo
Douglas W
DW
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control*; D003131:Combined Modality Therapy; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D010957:Plasmids / Q000008:administration & dosage; D011817:Rabbits; D013234:Stem Cells / Q000166:cytology; D015607:Stents; D014463:Ultrasonography; D042442:Vascular Endothelial Growth Factors / Q000032:analysis / Q000235:genetics*
D042442:Vascular Endothelial Growth Factors; D009569:Nitric Oxide