© 2001 American Heart Association, Inc.
Integrative Physiology |
Mouse Carotid Artery Ligation Induces Platelet-Leukocyte–Dependent Luminal Fibrin, Required for Neointima Development
From the Center for Molecular and Vascular Biology (T.K., H.R.L., I.V., J.V., M.F.H.), University of Leuven and Center for Transgene Technology and Gene Therapy (M.D.), Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.
Correspondence to Marc F. Hoylaerts, PhD, Center for Molecular and Vascular Biology, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail Marc.Hoylaerts{at}med.kuleuven.ac.be
Abstract—The
relationship between platelet and leukocyte activation, coagulation,
and neointima development was investigated in noninjured murine blood
vessels subjected to blood stasis. The left common carotid artery of
C57BL/6J mice was ligated proximal to the bifurcation. Tissue-factor
expression in luminal leukocytes progressively increased over 2 weeks.
On day 3 after ligation, in addition to infiltrated granulocytes,
platelet microthrombi and platelet-covered leukocytes as well as
tissue-factor–positive fibrin deposits lined the endothelium. Maximal
neointima formation in carotid artery cross sections of control mice
equaled 28±3.7% (n=11) and 42±5.1% (n=8) of the internal elastic
lamina cross-sectional area 1 and 2 weeks after ligation. In
FVIII-/- mice, stenosis was
significantly lower 1 (11±3.6%, n=8) and 2 (21±4.7%, n=7) weeks
after ligation (both P<0.01
versus background-matched controls). In
u-PA-/- mice, luminal stenosis was
significantly higher 1 (38±7.0%, n=7) and 2 (77±5.6%, n=6) weeks
after ligation (P<0.05 and
P<0.01, respectively, versus
matched controls). In
2-AP-/- mice,
stenosis was lower at 1 week (14±2.6%, n=7,
P<0.01) but not at 2 weeks.
Responses in tissue-type plasminogen activator or plasminogen activator
inhibitor-1 gene–deficient mice equaled that in controls. Reducing
plasma fibrinogen levels in controls with ancrod or inducing partial
thrombocytopenia with busulfan resulted in significantly less
neointima, but inflammation was inhibited only in busulfan-treated
mice. We conclude that stasis induces platelet activation, leading to
microthrombosis and platelet-leukocyte conjugate formation, triggering
inflammation and tissue-factor accumulation on the carotid artery
endothelium. Delayed coagulation then results in formation of a fibrin
matrix, which is used by smooth muscle cells to migrate into the
lumen.
Key Words: platelets • fibrinogen • thrombosis • neointima • tissue factor
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