Matrix metalloproteinases can facilitate the heparanase-induced promotion of phenotypic change in vascular smooth muscle cells

Previous studies from this laboratory have shown that degradation of hepara n sulphate proteoglycan by both living macrophages and macrophage lysosomal heparanase induces phenotypic change of vascular smooth muscle cells (SMC) from a high volume fraction of myofilaments (V(v)myo) to a low V(v)myo [Ca mpbell et al. Exp Cell Res 1992; 200: 156-167]. The aim of this study was t o determine whether matrix metalloproteinase (MMP) activity is also involve d in the induction of SMC phenotypic change by macrophages. A specific inhi bitor of MMPs (BB94) was able to block macrophage-induced SMC phenotypic ch ange and subsequent DNA synthesis in freshly dispersed SMC seeded in primar y culture at confluent density. The inhibitor did not block these SMC chang es when SMC were seeded at low density without macrophages nor did it block heparanase activity directly. We also determined whether heparanase and MM P activities are upregulated together in vivo. Artery homogenates were anal ysed in a heparanase enzyme assay and for MMPs using zymograms. Increased h eparanase activity was observed 3-14 days following balloon catheter injury of rabbit carotid arteries, and returned to control levels 6 weeks after i njury. Active MMP2 was induced with heparanase after injury. MMP9 induction was also apparent 6 h after injury. Immunohistology on sections of these a rteries showed the presence of MMP1, 2, 3 and 9 with these MMPs being stron gly induced in the intima 7 days after balloon catheter injury. Both hepara nase and MMP activities were also present in human end-stage complex lesion s from coronary arteries, carotid endarterectomies and abdominal aortic ane urysms. Because MMPs and heparanase are expressed at the same time, it is p ossible that MMPs facilitate heparanase activity in promotion of phenotypic modulation of SMC in vivo during neointimal thickening following injury an d in atherosclerotic lesions. (C) 1999 Elsevier Science Ireland Ltd. All ri ghts reserved.