Author + information
- Received February 11, 1994
- Revision received June 3, 1994
- Accepted July 19, 1994
- Published online December 1, 1994.
- Hirofumi Sawa, MD,
- Craig Lundgren, MD,
- Burton E. Sobel, MD, FACC and
- Satoshi Fujii, MD∗
- ↵∗Present address and address for correspondence: Dr. Satoshi Fujii, University of Vermont College of Medicine, C-350 Given Building, Burlington, Vermont 05405.
Objectives. This study was performed to determine whether altered gene expression of plasminogen activator inhibitor type I (PAI-1) occurs within the arterial wall after experimentally induced balloon injury.
Background. PAI-1, known to inhibit fibrinolysis in the circulation and to be present within atherosclerotic vessels, may influence proteolysis in the arterial wall and neointimal formation after angioplasty.
Methods. In rabbit carotid arteries subjected to balloon injury, both PAI-1 gene and protein expression were assayed sequentially with the use of Northern blotting, in situ hybridization and immunohistochemical studies.
Results. In uninjured, normal vessels PAI-1 messenger ribonucleic acid (mRNA) was not detectable by Northern blotting or in situ hybridization. However, injury was followed within 3 h by increases in PAI-1 mRNA (3.2 kb) of 5.9-fold compared with that in contralateral control carotid arteries (Northern blots). PAI-1 mRNA was detectable by in 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 detected immunohistochemically. In vessels maintained in organ culture after balloon injury in vivo, sustained increases in PAI-1 activity appeared in conditioned media as well.
Conclusions. Our results indicate that balloon injury simulating angioplasty in patients induces intramural expression of PAI-1 in vascular smooth muscle and endothelial cells. The decreased cell surface fibrinolytic activity likely to result from the increased PAI-1 expression may initiate or exacerbate mural thrombosis. Accordingly, excessive stimulation with clot-associated mitogens may stimulate vascular smooth muscle cell proliferation, which, coupled with increased accumulation of extracellular matrix attributable to decreased plasmin-mediated degradation, may contribute to restenosis.
☆ This study was supported in part by Grant HL-17646, SCOR in Coronary and Vascular Diseases, National Heart, Lung, and Blond Institute, National Institutes of Health, Bethesda, Maryland and a grant-in-aid to Dr. Fujii from the American Heart Association, Missouri Affiliate.
- Received February 11, 1994.
- Revision received June 3, 1994.
- Accepted July 19, 1994.