Shear force regulates matrix metalloproteinase activity in human saphenousvein organ culture

Background. Development of vein graft intimal hyperplasia has been related both to shear force and to the activity of matrix metalloproteinases (MMPs) . Little data are available regarding the effects of shear on MMP expressio n and activity. The aim of this study was to examine the relationship among shear force, metalloproteinase activity, and intimal thickening in human s aphenous vein segments maintained in organ culture. Materials and methods. Segments of human saphenous vein were cultured under static conditions, or perfused under low-flow and high-flow conditions in a perfusion apparatus for 7 days. Metalloproteinase levels and activities w ere measured using ELISA and substrate gel zymography, respectively. Intima l thickening was determined by morphometric analysis. Results were compared with control vein tissue, which was not subjected to organ culture, using a one-way ANOVA. Results. A 13% increase in proteolyti c activity was noted on substrate gel zymography at 68-72 kDa in high-flow vein tissue. The protein content of MMP-8, MMP-9, tissue inhibitor of metal loproteinase-1 (TIMP-1), and TIMP-2 was increased in high-flow vein tissue by 21%, 126%, more than 100-fold, and 86%, respectively. In culture media b athing the outside of the vein, TIMP-2 was increased in high-flow specimens , while TIMP-1 was inversely related to flow rate. Intimal thickening was d irectly related to flow rates, and was progressively increased in the low-f low and high-flow groups by 3-fold and 4-fold, respectively. Conclusions. Metalloproteinase levels in human saphenous vein cultures are related to shear force. MMP levels and activity correlate with the degree o f intimal thickening. This model may provide a valuable tool for the analys is of physical forces and their influence on intimal thickening in human sa phenous vein. (C) 2001 Academic Press.