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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1753.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Adenovirus-Mediated VEGF Gene Therapy Enhances Venous Thrombus Recanalization and Resolution

B. Modarai; J. Humphries; J.A. Gossage; M. Waltham; K.G. Burnand; G.S. Kanaganayagam; A. Afuwape; E. Paleolog; A. Smith; A. Wadoodi

From King’s College London, Academic Dept. of Surgery (B.M., J.H., J.A.G., M.W., K.G.B., A.W., A.S.) and Dept. of Cardiology (G.S.K.) Cardiovascular Division, st. Thomas’ Hospital, London, UK; and the Kennedy Institute of Rheumatology (A.A., E.P.), Imperial College London, UK.

Correspondence to Dr Alberto Smith, Academic Department of Surgery, St Thomas’ Hospital, 1st Floor, North Wing, London SE1 7EH, United Kingdom. E-mail alberto.smith{at}kcl.ac.uk

Objective— Rapid thrombus recanalization reduces the incidence of post–thrombotic 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.

Key Words: thrombosis • angiogenesis • gene therapy