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.