Urokinase-type plasminogen activator promotes development of experimental restenosis

The temporal expression of urokinase-type plasminogen activator (uPA) and i ts receptor in balloon catheter-injured rat carotid arteries was examined u sing immunohistochemistry and reverse transcriptase-polymerase chain reacti on assay optimized to estimate mRNA levels. To define the role of proteolyt ic activity of uPA in stimulation of neointima formation perivascular admin istration of recombinant uPA forms in pluronic gel to the injured vessel wi th subsequent morphometric analysis were used. Results. Increased expressio ns of uPA, its receptor and proliferating cell nuclear antigen by SMCs were observed in the balloon catheter injured carotids compared to those in the uninjured vessels. Perivascular application to the injured vessel of pluro nic gel with recombinant uPA or recombinant uPA containing multiple mutatio ns in its growth factor domain, which functionally did not induce cell migr ation via receptor-dependent mechanisms, doubled the size of neointima and numbers of neointimal and medial SMCs 4 days after injury and caused greate r reductions in vessel lumen size than injury alone. In contrast to these t wo proteolytically active forms of uPA, the application of proteolytically inactive recombinant uPA containing in its catalytic site glutamine rather than histidine-204 did not affect neointima or lumen size, whereas neointim al SMC numbers tended to be above those observed in the vehicle treated inj ured vessels. The application of uPA neutralizing antibodies attenuated neo intima size 4 days after injury, reduced neointimal SMC numbers by approxim ately 50 percent and prevented much of the reduction in lumen size. Conclus ions. The proteolytic property of uPA is the major contributor to its abili ty to augment neointima formation early after balloon catheter injury to th e rat carotid artery. Antagonizing the proteolytic effects of uPA may be th erapeutically beneficial for attenuating neointimal growth.