Role of the fibrinolytic and matrix metalloproteinase systems in arterial neointima formation after vascular injury.
Circumstantial evidence has suggested an important role of the fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems in biological processes involving (extra)cellular proteolysis and/or matrix degradation, such as restenosis after vascular interventions in patients with atherothrombosis. The generation of mice with inactivation of main components of both systems and of suitable experimental models has allowed to study the interactions between both systems and their biological role in arterial neointima formation after vascular injury. During neointima formation after electric injury of the femoral artery, expression of MMP-2 and MMP-9 (gelatinase A and B) is strongly enhanced, independently of the presence or absence of plasminogen or of the physiological tissue-type (t-PA) or urokinase-type (u-PA) plasminogen activators. Activation of proMMP-2 occurs independently of plasmin, whereas proMMP-9 activation occurs via plasmin-dependent as well as plasmin-independent (MMP-3- or stromelysin-1-dependent) mechanisms. The temporal and topographic expression patterns of MMP-2, MMP-3, MMP-9, MMP-12 (metalloelastase) and MMP-13 (collagenase) after vascular injury are compatible with a role of MMPs in neointima formation. This is further substantiated by the finding that smooth muscle cell (SMC) migration and neointima formation after vascular injury is significantly enhanced in mice with deficiency of TIMP-1, the main physiological MMP inhibitor. In contrast, arterial neointima formation in mice is not affected by deficiency of alpha 2-antiplasmin, the main physiological plasmin inhibitor. Thus, SMC migration and neointima formation after vascular injury appear to be promoted by several MMP system components, that may be activated via plasmin-dependent or plasmin-independent mechanisms.
Lijnen
H R
HR
Center for Molecular and Vascular Biology Faculty of Medicine, Campus Gasthuisberg Katholieke Universiteit Leuven Herestraat 49, B-3000 Leuven.
D000818:Animals; D001808:Blood Vessels / Q000201:enzymology / Q000293:injuries* / Q000473:pathology; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis / Q000502:physiology*; D008666:Metalloendopeptidases / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D010958:Plasminogen / Q000378:metabolism
D010958:Plasminogen; D005341:Fibrinolysin; D008666:Metalloendopeptidases