FUNCTION OF THE PLASMINOGEN PLASMIN AND MATRIX METALLOPROTEINASE SYSTEMS AFTER VASCULAR INJURY IN MICE WITH TARGETED INACTIVATION OF FIBRINOLYTIC SYSTEM GENES/
Hr. Lijnen et al., FUNCTION OF THE PLASMINOGEN PLASMIN AND MATRIX METALLOPROTEINASE SYSTEMS AFTER VASCULAR INJURY IN MICE WITH TARGETED INACTIVATION OF FIBRINOLYTIC SYSTEM GENES/, Arteriosclerosis, thrombosis, and vascular biology, 18(7), 1998, pp. 1035-1045
The matrix metalloproteinase (MMP) system, which may be activated via
the plasminogen (Plg)/plasmin system, is claimed to play a role in mat
rix degradation and smooth muscle cell migration. To test the role of
both systems, expression of fibrinolytic and gelatinolytic activity wa
s quantified after vascular injury in mice with targeted inactivation
of tissue-type Pig activator (tPA(-/-)), urokinase-type Pig activator
(uPA(-/-)), or Pig (Plg(-/-)). Neointima formation 1 week after vascul
ar injury was impaired in uPA(-/-) and Plg(-/-) mice compared with wil
d-type (WT) mice or tPA-/- mice (reduction of neointimal area to 30% a
nd 10% of WT, respectively). Cell accumulation at the borders of the i
njury was significantly (P<0.01) impaired compared with that in WT mic
e. One week after injury of the femoral artery, tPA-mediated fibrinoly
tic activity in arterial sections or extracts of WT, uPA(-/-), or Plg(
-/-) mice was not altered, whereas uPA activity levels in tPA(-/-) and
Plg(-/-) mice were 2- to 3-fold. higher than in uninjured controls. T
otal levels (latent plus active) of MMP-2 (gelatinase A) were increase
d by 2-to 3-fold, whereas the contribution of active MMP-2 represented
38% to 63% of the total in the different genotypes, MMP-9 (gelatinase
B) was not detectable in the majority of control arteries, whereas to
tal MMP-9 levels after injury were dramatically increased (up to 50-fo
ld above the detection limit). Active MMP-9 represented 20% to 46% of
total MMP-9 in WT, tPA(-/-), and uPA(-/-) mice but was not consistentl
y detectable in Plg(-/-) mice. Similar results were obtained in caroti
d arteries. Thus, the unaltered ratios of active and latent MMP-2 sugg
est that proMMP-2 activation may occur;.in the absence of tPA, uPA, or
Pig, whereas no active MMP-9 was detected in the absence of Pig. The
data of this study confirm a role for uPA and Pig but not for tPA in s
mooth muscle cell migration and neointima formation after vascular inj
ury and indicate that impairment of these phenomena may occur despite
the observed increases in MMP-2 or MMP-9 levels after vascular injury.