INCREASED INTRAMURAL EXPRESSION OF PLASMINOGEN-ACTIVATOR INHIBITOR TYPE-1 AFTER BALLOON INJURY - A POTENTIAL PROGENITOR OF RESTENOSIS

Objectives. This study was performed to determine whether altered gene expression of plasminogen activator inhibitor type 1 (PAT-I) occurs w ithin the arterial wall after experimentally induced balloon injury. B ackground. PAI-1, known to inhibit fibrinolysis in the circulation and to be present within atherosclerotic vessels, may influence proteolys is in the arterial wall and neointimal formation after angioplasty. Me thods. In rabbit carotid arteries subjected to balloon injury, both PA I-1 gene and protein expression were assayed sequentially with the use of Northern blotting, in situ hybridization and immunohistochemical s tudies. Results. In uninjured, normal vessels PAI-1 messenger ribonu c leic acid (mRNA) was not detectable by Northern blotting or in situ hy bridization. However, injury was followed within 3 h by increases in P AI-1 mRNA (3.2 kb) of 5.9 fold compared with that in contralateral con trol carotid arteries (Northern blots). PAI-I mRNA was detectable by i n situ hybridization early after injury first in adventitia; after 24 h it was particularly prominent in the media. From 1 to 4 weeks after injury it was consistently detectable and was localized in neointimal vascular smooth muscle and endothelial cells at a time when neointimal thickening was marked. Cells of both types exhibited PAI-1 protein de tected immunohistochemically. In vessels maintained in organ culture a fter balloon injury in vivo, sustained increases in PAI-1 activity app eared in conditioned media as well. Conclusions. Our results indicate that balloon injury simulating angioplasty in patients induces intramu ral expression of PAI-1 in vascular smooth muscle and endothelial cell s. The decreased cell surface fibrinolytic activity likely to result f rom the increased PAI-1 expression may initiate or exacerbate mural th rombosis. Accordingly, excessive stimulation with clot-associated mito gens may stimulate vascular smooth muscle cell proliferation, which, c oupled with increased accumulation of extracellular matrix attributabl e to decreased plasmin-mediated degradation, may contribute to resteno sis.