title: Mouse carotid artery ligation induces platelet-leukocyte-dependent luminal fibrin, required for neointima development.
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 alpha(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.
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Kawasaki
authors.forename: M
authors.initials: M
authors.lastname: Dewerchin
authors.forename: H R
authors.initials: HR
authors.lastname: Lijnen
authors.forename: I
authors.initials: I
authors.lastname: Vreys
authors.forename: J
authors.initials: J
authors.lastname: Vermylen
authors.forename: M F
authors.initials: MF
authors.lastname: Hoylaerts
mesh_terms: D000347:Afibrinogenemia / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D001777:Blood Coagulation / Q000276:immunology; D001792:Blood Platelets / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002339:Carotid Arteries / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005337:Fibrin / Q000378:metabolism*; D020141:Hemostatic Disorders / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007962:Leukocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008026:Ligation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D015539:Platelet Activation; D013921:Thrombocytopenia / Q000139:chemically induced / Q000378:metabolism; D013925:Thromboplastin / Q000096:biosynthesis; D013927:Thrombosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology
chemical_list: D005337:Fibrin; D013925:Thromboplastin