Published online before print June 21, 2004, doi: 10.1161/01.CIR.0000133324.38115.0A
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(Circulation. 2004;110:36-45.)
© 2004 American Heart Association, Inc.
Original Articles |
Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents
An Alternative Strategy for Inhibition of Restenosis
From the Department of Medicine (Cardiovascular Research), St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass; Department of Pathology (F.O.T), University of Texas, San Antonio, Tex; Center for Learning and Memory (P.K.), Massachusetts Institute of Technology, Cambridge, Mass; and Biocompatibles UK Limited (S.W., L.K., P.W.S.), Surrey, UK.
Correspondence to Douglas W. Losordo, MD, Chief of Cardiovascular Research, St Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail douglas.losordo{at}tufts.edu
Received November 1, 2002; de novo received February 23, 2004; revision received March 16, 2004; accepted March 19, 2004.
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.
Methods and Results— phVEGF 2-plasmid (100 or 200 µg 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 mm2, 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.
Key Words: gene therapy • endothelium • restenosis
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