Vascular endothelial growth factor naked DNA gene transfer enhances thrombus recanalization and resolution

Abstract

ObjectivesEnhancing thrombus resolution may reduce the long-term complications of venous thrombosis. The aim of this study was to examine whether a sustained release of vascular endothelial growth factor (VEGF) would further improve thrombus recanalization.MethodsInferior caval vein thrombosis was induced in a cohort of 21 male Wistar rats. A plasmid encoding the human VEGF gene (phVEGF) was injected directly into thrombus (30 to 50 μg) and the muscle adjacent to the inferior vena cava (300 to 400 μg). A plasmid containing the gene encoding β-galactosidase (pCMVβ) was injected into the same sites of a separate cohort of rats to act as a control. Tissues were harvested after 1 and 2 weeks, and β-galactosidase activity was measured to estimate transfection efficiency. Muscle and serum VEGF were measured by enzyme-inked immunosorbent assay. Thrombus size, recanalization, and organization were determined by computer-assisted image analysis.ResultsThe efficiency of control plasmid transfection into muscle was about 1%. No serum hVEGF was detected in phVEGF- or pCMVβ-treated animals. Significantly raised levels of hVEGF (P < .01) were detected in the muscle injected with phVEGF after 2 weeks compared with control muscle. There was a significant reduction in thrombus size of 23% (P < .05) and 48% (P < .001) in phVEGF-treated animals compared with pCMVβ-treated controls after 1 and 2 weeks, respectively. Thrombus recanalization was a significantly greater in the phVEGF-treated group after 2 weeks (mean 19% ± 2% [SEM]) compared with controls (mean 13% ± 2%, P < .01). There were no differences in the thrombus organization score.ConclusionVEGF gene therapy of venous thrombus resulted in smaller thrombi with greater recanalization. Angiogenic gene therapy may form the basis of a novel treatment that may improve the resolution of venous thrombi.Clinical RelevanceDeep vein thrombosis may lead to residual venous obstruction or reflux and result in post-thrombotic complications that are debilitating and have a substantial socioeconomic impact. Enhancing the resolution of venous thrombi may reduce post thrombotic complications