Increased Secretion of Basement Membrane–Degrading Metalloproteinases in Pig Saphenous Vein Into Carotid Artery Interposition Grafts

Abstract

Late saphenous vein bypass graft failure in humans involves medial and neointimal thickening as the result of migration and proliferation of vascular smooth muscle cells (SMCs). Recent work on angioplasty indicates that basement membrane-degrading metalloproteinases (MMPs) cooperate with growth factors to mediate SMC migration and proliferation. We sought evidence here for a similar role in experimental vein grafts in pigs. Tissue levels and secretion of MMP-2 and MMP-9 were compared by quantitative zymography in veins and grafts removed 2 to 168 days after implantation. Pro and active forms of MMP-2 were present in veins, but levels were increased in vein grafts after 7 days (4- and 6-fold, respectively) and 28 days (3-fold for both), returning to values in veins after 168 days. MMP-9 was not detected in veins, was increased in grafts after 2 days, further increased after 7 days (6-fold) and 28 days (15-fold), and declined to undetectable levels by 168 days. Immunocytochemistry detected increased expression of MMP-2 and MMP-9 with the same time course. MMP-2 was widely distributed, whereas MMP-9 was concentrated in highly proliferative SMCs at the superficial layers of the thickened neointima. We conclude that increased production of the basement membrane-degrading MMP-2 and MMP-9 spanned the period of neointima formation and SMC proliferation in experimental vein grafts. MMPs therefore constitute new therapeutic targets for reducing late vein graft failure.