Temporal and topographic matrix metalloproteinase expression after vascular injury in mice

Temporal and topographic expression of matrix metalloproteinases (MMPs) aft er perivascular electric injury was studied in wild-type (WT) and urokinase -deficient (u-PA(-/-)) mice. Neointima formation after injury of the femora l artery was significantly reduced in u-PA(-/-) mice as compared to WT mice (area of 0.002 +/- 0.0007 mm(2) versus 0.008 +/- 0.002 mm(2) at 3 weeks af ter injury; p <0.001), associated with impaired cellular migration (nuclear cell counts of 44 +/- 5 versus 82 +/- 9 in cross-sectional areas; p <0.001 ). Zymographic and/or microscopic analysis indicated that MMP expression gradu ally increased to reach a maximum at 1 to 2 weeks after vascular injury. In general, MMP levels were lower in u-PA(-/-) than in WT mice. In non-injure d arteries, MMP-2 (gelatinase A) and MMP3 (stromelysin-l) were produced mai nly by adventitial fibroblasts and/or non-contractile smooth muscle cells ( SMC). One week after injury, MMP-2 and MMP3 levels were enhanced due to an increased number and size of producing cells; 2 to 3 weeks after injury, MM P-2 and MMP3 were produced also by some contractile SMC, which stained with alpha-actin antiserum. MMP-9 (gelatinase B), MMP-12 (metalloelastase) and MMP-13 (collagenase3) were found in macrophages located mainly in the adven titia. Immunogold electron microscopic examination revealed that MMP-2 was located predominantly in association with the cell surface of fibroblasts o r SMC, while MMP-9 and MMP-12 were located in well defined storage granules within macrophages. MMP-2, MMP-3 and MMP-13, but not MMP-9 or MMP-12, were also found extracellularly, associated with elastin-containing structures (MMP-2), with the basement membrane and occasionally with collagen fibres ( MMP3), or with proteoglycans, collagen and elastin (MMP-13). The temporal and topographic expression pattern of MMPs after vascular inju ry, coinciding with smooth muscle cell migration and neointima formation, t hus is compatible with a role in vascular remodeling.