Improved endothelialization of small-diameter ePTFE grafts through growth factor therapy.

Abstract

Background: Prosthetic vascular grafts in humans characteristically lack confluent endothelialization regardless the duration of implantation. Use of high-porosity grafts has been proposed as a way to induce endothelialization through transgraft capillarization, although early experiments failed to show increased healing in man. Objectives: We hypothesized that transduction of tissues around the prosthetic conduit with vectors encoding VEGF Receptor-2 (VEGFR2) ligands would augment transinterstitial capillarization and induce luminal endothelialization of high-porosity PTFE grafts. Methods: Fifty-two NZW rabbits received 87 ePTFE uni- or bilateral end-to-end interposition grafts in carotid arteries. Rabbits were randomized to local therapy with adenoviruses encoding AdVEGF-A165, AdVEGF-A109 or control AdLacZ and analyzed at 6 and 28d after surgery by contrast-enhanced ultrasound and histology. Results: AdVEGF-A165 and AdVEGF-A109 dramatically increased perfusion in perigraft tissues at 6d (14.2±3.6 or 16.7±2.6- fold increases, P<0.05 and P<0.01). At 28d the effect was no longer significantly higher than baseline. At 6d no luminal endothelialization was observed in any of the groups. At 28d, AdVEGF-A109 and AdVEGF-A165 treated animals showed enhanced ingrowth of transinterstitial capillaries (66.0±13.7% and 77.4±15.7% of graft thickness vs. 44.7±24.4% in controls, P<0.05) and improved luminal endothelialization (11.2±26.3% and 11.4±22.2%, AdVEGF-A109 and AdVEGF-A165 vs. 0% in controls, P<0.05). No increased stenosis was observed in the treatment groups as compared to LacZ controls. Conclusions: This study suggests that transient local overexpression of VEGFR2 ligands in the peri-implant tissues at time of graft implantation is a novel strategy to increase endothelialization of high-porosity ePTFE vascular grafts and improve the patency of small-diameter vascular prostheses.