Adenovirus-mediated VEGF gene therapy enhances venous thrombus recanalization and resolution

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 mm(2) to 22.0 +/- 4.0 mm(2), 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 mm(2) to 8.7 +/- 1.4 mm(2), 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.