Inhibition of smooth muscle cell migration and neointima formation in vein grafts by overexpression of matrix metalloproteinase-3

ObjectiveSaphenous vein grafts suffer from neointima formation following bypass surgery. Matrix metalloproteinases (MMPs) play important roles in this process. We examined MMP-3 for its therapeutic potential to prevent smooth muscle cell migration and neointima formation in venous bypass grafts using adenovirus-mediated gene transfer.MethodsHuman aortic smooth muscle cells (HASMC) were transduced with adenoviral vectors encoding ß-galactosidase (AVEßgal) or human MMP-3 (hMMP-3), and characterized for migration in the amniotic membrane stroma as an in vitro model of the vascular wall. Cholesterol-fed New Zealand white rabbits underwent jugular vein bypass grafting into carotid arteries. Before insertion, grafts were incubated ex vivo with either AVEßgal or hMMP-3. Transgene expression was characterized by immunohistochemistry and in situ zymography. Grafts (n = 6) were explanted after 28 days and intimal hyperplasia was quantified.ResultsMigration of HASMC was significantly reduced when transduced with hMMP-3 compared to controls (P < .001). Immunocytochemistry of hMMP-3 transduced venous grafts localized this protein to the intima. In situ-zymography showed increased MMP activity in the intima of hMMP-3 transfected grafts. Stenosis degree (P = .001), intima/media-ratio (P = .023) and lesion thickness (P = .003) were significantly reduced in grafts transduced with Ad.MMP-3 in comparison to controls. There was no difference inside control groups.ConclusionMMP-3 overexpression inhibits formation of intimal hyperplasia in arterialized vein grafts. Adenovirus mediated gene transfer of MMP-3 may be of clinical use to prevent vein graft stenosis following bypass surgery.

Clinical RelevanceAlthough vein grafts are conduits of choice for lower extremity and coronary bypass graft surgery, patency rates of vein grafts remain unsatisfactory. The underlying mechanism for graft stenosis and occlusion is the development of intimal hyperplasia, caused by smooth muscle cell migration from the vascular media into the intima. The inhibition of smooth muscle cell migration by gentherapeutic strategies, clinically applicable to veins after harvesting and before graft insertion, may lead to bypass grafts with improved patency. Here we examine the effect of overexpression of MMP-3 both in vitro on smooth muscle cell migration and in vivo on development of intimal hyperplasia, aimed to develop pre-clinical strategies for prevention of vein graft stenosis.