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

Objective: Saphenous 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. Methods: Human aortic smooth muscle cells (HASMC) were transduced with adenoviral vectors encoding beta-galactosidase (AVE beta gal) 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 AVE beta gal 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. Results. Migration 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. Conclusion: MMP-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. (J Vasc Surg 2009;49:750-8.)