(Circulation. 2001;103:576.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Plasminogen Activator Inhibitor-1 and Its Cofactor Vitronectin Stabilize Arterial Thrombi After Vascular Injury in Mice
From the Department of Vascular Biology, The Scripps Research Institute, La Jolla, Calif.
Correspondence to David J. Loskutoff, PhD, The Scripps Research Institute, Department of Vascular Biology, VB-3, 10550 N Torrey Pines Rd, La Jolla, CA 92037. E-mail loskutof{at}scripps.edu
Background—The origin and contribution of plasminogen activator inhibitor-1 (PAI-1) and its cofactor vitronectin (VN) to arterial thrombosis/thrombolysis in vivo is controversial.
Methods and
Results—Ferric chloride was used to induce
carotid artery injury in 97 wild-type (WT), 84 PAI-1-/-, and 84
VN-/- mice. Complete thrombotic occlusion was observed in 70% of
PAI-1-/- mice versus 92% of WT
(P<0.001) and 87% of
VN-/- (P=0.015) mice. In
vessels that occluded, mean times to occlusion were significantly
longer in PAI-1-/- than in WT or VN-/- mice. The initial
thrombotic response of VN-/- mice was similar to that of WT mice,
but their thrombi were unstable and frequently embolized. As a result,
the patency rate of carotid vessels 30 minutes after injury was as high
in VN-/- mice (36%) as in PAI-1-/- mice (which demonstrate
progressive thrombolysis) and significantly higher than that of WT mice
(12%; P=0.013). Histochemical
and reverse transcription–polymerase chain reaction studies revealed
an early upregulation of PAI-1 mRNA and protein expression in the
thrombus and the vessel wall, which persisted for 
1 week. VN protein
also accumulated after injury, but VN mRNA levels remained low at all
times.
Conclusions—PAI-1 and VN participate in the thrombotic response to arterial injury by preventing premature thrombus dissolution and embolization. The accumulation of PAI-1 in the thrombus/vessel wall after injury may result, at least in part, from local synthesis, whereas the VN protein appears to be derived from plasma.
Key Words: carotid arteries • genes • fibrinolysis • embolism
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