Abstract
Current gene therapy and tissue engineering protocols suffer from a number of inherent limitations. In this study, we examine the feasibility of a new approach for the treatment of vascular thrombosis: in vivo tissue engineering. Rabbit femoral veins were transfected in situ with either a previously characterized adenoviral-construct-expressing tissue plasminogen activator or a viral (adenoviral-construct-expressing beta-galactosidase) or nonviral (buffer) control and used as cross sections (n = 3). Treated veins were then harvested and grafted into the ipsilateral common femoral artery as an interposition vein graft. A potent stimulus for thrombus formation was then introduced into the recipient artery downstream of the graft. Six days later, the rabbits were sacrificed, and the grafts and downstream arteries were harvested. Vessel segments were then examined for thrombus according to defined anatomic zones. Transfection efficiency and presence of smooth muscle cells in the vein graft were also evaluated. The engineered vein graft showed a significant reduction in thrombus formation within both the graft and the downstream artery relative to nonviral (buffer) and viral (adenoviral-Rous sarcoma virus beta-galactosidase [Adv/RSV-betagal]) controls. Underlying endothelial cell transfection efficiency of 90% was observed in viral controls (Adv/RSV-betagal). A 2.4-fold increase in smooth muscle alpha-actin positive cells in the engineered vein graft was seen compared with nonviral (phosphate-buffered saline) controls. A 10-fold increase in smooth muscle alpha-actin-positive cells in the engineered vein graft relative to viral (Adv/RSV-betagal) controls was also observed. In vivo tissue engineering is a new paradigm in molecular medicine that is a viable alternative to conventional gene therapy and tissue engineering for the treatment of vascular thrombosis.
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