Type 1 plasminogen activator inhibitor binds to fibrin via vitronectin
Type 1 plasminogen activator inhibitor (PAI-1), the primary inhibitor of tissue-type plasminogen activator (t-PA), circulates as a complex with the abundant plasma glycoprotein, vitronectin. This interaction stabilizes the inhibitor in its active conformation. In this report, the effects of vitronectin on the interactions of PAI-1 with fibrin clots were studied. Confocal microscopic imaging of platelet-poor plasma clots reveals that essentially all fibrin-associated PAI-1 colocalizes with fibrin-bound vitronectin. Moreover, formation of platelet-poor plasma clots in the presence of polyclonal antibodies specific for vitronectin attenuated the inhibitory effects of PAI-1 on t-PA-mediated fibrinolysis. Addition of vitronectin during clot formation markedly potentiates PAI-1-mediated inhibition of lysis of 125I-labeled fibrin clots by t-PA. This effect is dependent on direct binding interactions of vitronectin with fibrin. There is no significant effect of fibrin-associated vitronectin on fibrinolysis in the absence of PAI-1. The binding of PAI-1 to fibrin clots formed in the absence of vitronectin was characterized by a low affinity (Kd ~ 3.5 μM) and rapid loss of PAI-1 inhibitory activity over time. In contrast, a high affinity and stabilization of PAI-1 activity characterized the cooperative binding of PAI- 1 to fibrin formed in the presence of vitronectin. These findings indicate that plasma PAI-1-vitronectin complexes can be localized to the surface of fibrin clots; by this localization, they may modulate fibrinolysis and clot reorganization.
Publication Source (Journal or Book title)
Journal of Biological Chemistry
Podor, T., Peterson, C., Lawrence, D., Stefansson, S., Shaughnessy, S., Foulon, D., Butcher, M., & Weitz, J. (2000). Type 1 plasminogen activator inhibitor binds to fibrin via vitronectin. Journal of Biological Chemistry, 275 (26), 19788-19794. https://doi.org/10.1074/jbc.M908079199