Vascular release of plasminogen activator inhibitor-1 impairs fibrinolysis during acute arterial thrombosis in mice.
The role of plasminogen activator inhibitor-1 (PAI-1) in the plasma, blood platelets, and vessel wall during acute arterial thrombus formation was investigated in gene-deficient mice. Photochemically induced thrombosis in the carotid artery was analyzed via transillumination. In comparison to thrombosis in C57BL/6J wild-type (wt) mice (113 +/- 19 x 10(6) arbitrary light units [AU] n = 15, mean +/- SEM), thrombosis in PAI-1(-/-) mice (40 +/- 10 x 10(6) AU, n = 13) was inhibited (P <.01), indicating that PAI-1 controls fibrinolysis during thrombus formation. Systemic administration of murine PAI-1 into PAI-1(-/-) mice led to a full recovery of thrombotic response. Occurrence of fibrinolytic activity was confirmed in alpha(2)-antiplasmin (alpha(2)-AP)-deficient mice. The sizes of thrombi developing in wt mice, in alpha(2)-AP(+/-) and alpha(2)-AP(-/-) mice were 102 +/- 35, 65 +/- 8.1, and 13 +/- 6.1 x 10(6) AU, respectively (n = 6 each) (P <.05), compatible with functional plasmin inhibition by alpha(2)-AP. In contrast, thrombi in wt mice, t-PA(-/-) and u-PA(-/-) mice were comparable, substantiating efficient inhibition of fibrinolysis by the combined PAI-1/alpha(2)-AP action. Platelet depletion and reconstitution confirmed a normal thrombotic response in wt mice, reconstituted with PAI-1(-/-) platelets, but weak thrombosis in PAI-1(-/-) mice reconstituted with wt platelets. Accordingly, murine (wt) PAI-1 levels in platelet lysates and releasates were 0.43 +/- 0.09 ng/10(9) platelets and plasma concentrations equaled 0.73 +/- 0.13 ng/mL. After photochemical injury, plasma PAI-1 rose to 2.9 +/- 0.7 ng/mL (n = 9, P <.01). The plasma rise was prevented by ligating the carotid artery. Hence, during acute thrombosis, fibrinolysis is efficiently prevented by plasma alpha(2)-AP, but also by vascular PAI-1, locally released into the circulation after endothelial injury.
Kawasaki
T
T
Center for Molecular and Vascular Biology, University of Leuven, and Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.
Dewerchin
M
M
Lijnen
H R
HR
Vermylen
J
J
Hoylaerts
M F
MF
D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D002341:Carotid Artery Thrombosis / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010777:Photochemistry; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D010976:Platelet Count; D011994:Recombinant Proteins / Q000494:pharmacology; D013921:Thrombocytopenia / Q000235:genetics / Q000503:physiopathology; D010959:Tissue Plasminogen Activator / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator