Neointimal hyperplasia on a cell-seeded polytetrafluoroethylene graft is promoted by transfer of tissue plasminogen activator gene and inhibited by transfer of nitric oxide synthase gene

ObjectiveThe objective of this study was to examine the effect of tissue plasminogen activator (tPA) and endothelial nitric oxide synthase (eNOS) on thrombosis and neointimal hyperplasia on a polytetrafluoroethylene (PTFE) graft seeded with smooth muscle cells (SMCs).MethodsSMCs retrovirally transduced with tPA and eNOS genes were seeded on PTFE grafts and then implanted into the infrarenal rabbit aorta. Thrombosis and neointimal hyperplasia on the grafts were examined after 30 and 100 days of implantation.ResultsAt 30 days of implantation, thrombus was observed on the luminal surface of both unseeded and SMC seeded control grafts, whereas grafts seeded with SMCs secreting tPA were nearly free of thrombus. At 100 days, the neointima on grafts seeded with tPA transduced SMCs was significantly thicker (925 ± 150 μm, n = 5) than neointima on the other grafts (range, 132 to 374 μm; P < .001). Neointima thickness on grafts seeded with eNOS transduced SMCs (154 ± 27 μm) was similar to that of unseeded grafts (132 ± 16 μm, P > .05); both were thinner than those on grafts seeded with SMCs transduced with only lacZ gene (287 ± 35 μm). The ratio of seeded cells in the neointima was significantly higher on SMC/tPA grafts (46% ± 8%) than SMC/NOS grafts (21% ± 6%, P < .05), indicating tPA transduced cells proliferated more than eNOS transduced cells.ConclusionsEngineered tPA expression in seeded SMCs causes significantly more neointimal hyperplasia, despite the favorable inhibition of luminal thrombus. eNOS expression in the seeded cells inhibits neointimal hyperplasia.Clinical relevanceVascular prosthetic grafts are vulnerable to thrombosis and restenosis resulting in high incidence of limb loss when autogenous vein is not available. Modification of vascular prosthetic grafts to more closely mimic natural conditions may protect against clot formation and may have an immediate and prolonged effect on vascular surgical results. This study examined the patency of a prosthetic vascular graft by seeding the grafts with genetically engineered cells to prevent thrombosis and restenosis