on July 31, 2008
Published online before print July 31, 2008, doi: 10.1161/ATVBAHA.108.170571
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Submitted on March 7, 2006
Accepted on June 27, 2008
Adenovirus-Mediated VEGF Gene Therapy Enhances Venous Thrombus Recanalization and Resolution
B. Modarai ;
From the Academic Departments of Surgery (B.M., J.H., J.A.G., M.W., K.G.B., A.S.), and Cardiology (G.S.K.), Cardiovascular Division, St Thomas' Campus, King's College, and the Kennedy Institute of Rheumatology (A.A., E.P.), Imperial College, London, UK.
* To whom correspondence should be addressed. E-mail: alberto.smith{at}kcl.ac.uk.
Objective—Rapid thrombus recanalization reduces the incidence of postthrombotic complications. This study aimed to discover whether adenovirus-mediated transfection of the vascular endothelial growth factor gene (ad.VEGF) enhanced thrombus recanalization and resolution.
Methods and Results—In rats, thrombi were directly injected with either ad.VEGF (n=40) or ad.GFP (n=37). Thrombi in SCID mice (n=12) were injected with human macrophages transfected with ad.VEGF or ad.GFP. Thrombi were analyzed at 1 to 14 days. GFP was found mainly in the vein wall and adventitia by 3 days, but was predominantly found in cells within the body of thrombus by day 7. VEGF levels peaked at 4 days (376±299 pg/mg protein). Ad.VEGF treatment reduced thrombus size by >50% (47.7±5.1 mm2 to 22.0±4.0 mm2, P=0.0003) and increased recanalization by >3-fold (3.9±0.69% to 13.6±4.1%, P=0.024) compared with controls. Ad.VEGF treatment increased macrophage recruitment into the thrombus by more than 50% (P=0.002). Ad.VEGF-transfected macrophages reduced thrombus size by 30% compared with controls (12.3±0.89 mm2 to 8.7±1.4 mm2, P=0.04) and enhanced vein lumen recanalization (3.39±0.34% to 5.07±0.57%, P=0.02).
Conclusion—Treatment with ad.VEGF enhanced thrombus recanalization and resolution, probably as a consequence of an increase in macrophage recruitment.