FUNCTION OF THE PLASMINOGEN PLASMIN AND MATRIX METALLOPROTEINASE SYSTEMS AFTER VASCULAR INJURY IN MICE WITH TARGETED INACTIVATION OF FIBRINOLYTIC SYSTEM GENES/

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.