Background: Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) are thought to play critical roles in vascular remodeling after injury, with tPA mediating intravascular clot lysis and uPA modulating cell migration within the vessel wall. In human vascular disease, however, thrombus organization and neointimal formation are closely interrelated processes. This study examines the differential roles of tPA and uPA in these processes in mice.
Methods and results: Carotid artery injury and thrombosis were induced in wild-type (WT), uPA-deficient (uPA(-/-)), and tPA-deficient (tPA(-/-)) mice with the use of ferric chloride. The expression of uPA and tPA was significantly upregulated in the vessel wall of WT mice 1 week after injury, and compared with WT mice, uPA(-/-) and tPA(-/-) mice had lower carotid patency rates after injury. At 3 weeks, only 55% of uPA(-/-) mouse vessels were patent compared with 81% in tPA(-/-) mice and 100% in WT mice (P=0.014). Morphometric analysis of injured arterial segments revealed severe luminal stenosis (62+/-28%) in uPA(-/-) mice compared with their tPA(-/-) (16+/-12%) and WT (6.3+/-3.6%, P<0.001) counterparts. Moreover, although the vascular walls of WT mice and, particularly, tPA(-/-) mice developed a cell-rich multilayered neointima and media, the lumen of uPA(-/-) vessels remained obstructed with acellular unorganized thrombotic material, and their medial areas did not expand.
Conclusions: These results indicate that the roles of uPA and tPA in the arterial response to injury are different and more complex than previously assumed and emphasize the critical role of thrombus organization and resolution in neointimal formation and vascular pathology.