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Thromb Haemost 2011; 105(S 06): S3-S12
DOI: 10.1160/THS10-11-0730
Thrombosis and Haemostasis Supplement
Schattauer GmbH

Comparison of two murine models of thrombosis induced by atherosclerotic plaque injury

Béatrice Hechler
1   UMR_S949 INSERM, Université de Strasbourg, Etablissement Français du Sang-Alsace, Strasbourg, France
,
Christian Gachet
1   UMR_S949 INSERM, Université de Strasbourg, Etablissement Français du Sang-Alsace, Strasbourg, France
› Author Affiliations Financial support: This work was supported by INSERM, EFS, ARMESA (Association de Recherche et Développement en Médecine et Santé Publique), Fondation de France (Grant 2007001964), the Agence Nationale de la Recherche (grant ANR-06-PHYSIO-036–01) and the GIP « Pôle de compétitivité BioValley » in the frame of the HORUS project. BH is the recipient of a “contrat d’interface” between the EFS and INSERM. This work was also supported by an unrestricted educational grant from Eli Lilly and Daiichi Sankyo alliance to the University of Sheffield and to the Université de Strasbourg, in support of the European Platelet Academy.
Further Information

Publication History

Received: 15 November 2010

Accepted after major revision: 29 January 2011

Publication Date:
06 December 2017 (online)

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Summary

Arterial thrombosis occurs at sites of erosion or rupture of atherosclerotic vascular lesions. To better study the pathophysiology of this complex phenomenon, there is a need for animal models of localised thrombosis at sites of atherosclerotic lesions with closer resemblance to the human pathology as compared to commonly used thrombosis models in healthy vessels. In the present study, we describe and compare a new model of thrombosis induced by atherosclerotic plaque rupture in the carotid artery from ApoE-/- mice using a suture needle to a milder model of ultrasound-induced plaque injury. Needle injury induces atherosclerotic plaque rupture with exposure of plaque material and formation of a thrombus that is larger, nearly occlusive and more stable as compared to that formed by application of ultrasounds. These two models have common features such as the concomitant involvement of platelet activation, thrombin generation and fibrin formation, which translates into sensitivity toward both antiplatelet drugs and anticoagulants. On the other hand, they display differences with respect to the role of the platelet collagen receptor GPVI, the plaque rupture model being less sensitive to its inhibition as compared to the ultrasound-induced injury, which may be related to the amount of thrombin generated. These models represent an improvement as compared to models in healthy vessels and may help identify specific plaque triggers of thrombosis. They should therefore be useful to evaluate new antithrombotic targets.

Keywords

Animal models - antiplatelet agents - atherosclerosis - arterial thrombosis - atherothrombosis
 

  • References

  • 1 Day SM, Reeve JL, Myers DD. et al. Murine thrombosis models. Thromb Haemost 2004; 92: 486-494.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Denis C, Methia N, Frenette PS. et al. A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis. Proc Natl Acad Sci USA 1998; 95: 9524-9529.
    CrossrefPubMedGoogle Scholar
  • 3 Kurz KD, Main BW, Sandusky GE. Rat model of arterial thrombosis induced by ferric chloride. Thromb Res 1990; 60: 269-280.
    CrossrefPubMedGoogle Scholar
  • 4 Matsuno H, Uematsu T, Nagashima S. et al. Photochemically induced thrombosis model in rat femoral artery and evaluation of effects of heparin and tissue-type plasminogen activator with use of this model. J Pharmacol Methods 1991; 25: 303-317.
    CrossrefPubMedGoogle Scholar
  • 5 Westrick RJ, Winn ME, Eitzman DT. Murine models of vascular thrombosis (Eitzman series). Arterioscler Thromb Vasc Biol 2007; 27: 2079-2093.
    CrossrefPubMedGoogle Scholar
  • 6 Falati S, Gross P, Merrill-Skoloff G. et al. Real-time in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse. Nat Med 2002; 8: 1175-1181.
    CrossrefPubMedGoogle Scholar
  • 7 Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359: 938-949.
    CrossrefPubMedGoogle Scholar
  • 8 Nonne C, Lenain N, Hechler B. et al. Importance of platelet phospholipase Cgamma2 signaling in arterial thrombosis as a function of lesion severity. Arterioscler Thromb Vasc Biol 2005; 25: 1293-1298.
    CrossrefPubMedGoogle Scholar
  • 9 Celi A, Merrill-Skoloff G, Gross P. et al. Thrombus formation: direct real-time observation and digital analysis of thrombus assembly in a living mouse by confocal and widefield intravital microscopy. J Thromb Haemost 2003; 1: 60-68.
    CrossrefPubMedGoogle Scholar
  • 10 Hechler B, Nonne C, Eckly A. et al. Arterial thrombosis: relevance of a model with two levels of severity assessed by histologic, ultrastructural and functional characterization. J Thromb Haemost 2010; 8: 173-184.
    CrossrefPubMedGoogle Scholar
  • 11 Rosen ED, Raymond S, Zollman A. et al. Laser-induced noninvasive vascular injury models in mice generate platelet- and coagulation-dependent thrombi. Am J Pathol 2001; 158: 1613-1622.
    CrossrefPubMedGoogle Scholar
  • 12 Nieswandt B, Aktas B, Moers A. et al. Platelets in atherothrombosis: lessons from mouse models. J Thromb Haemost 2005; 3: 1725-1736.
    CrossrefPubMedGoogle Scholar
  • 13 Sachs UJ, Nieswandt B. In vivo thrombus formation in murine models. Circ Res 2007; 100: 979-991.
    CrossrefPubMedGoogle Scholar
  • 14 Barnes MJ, Farndale RW. Collagens and atherosclerosis. Exp Gerontol 1999; 34: 513-525.
    CrossrefPubMedGoogle Scholar
  • 15 Fernandez-Ortiz A, Badimon JJ, Falk E. et al. Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture. J Am Coll Cardiol 1994; 23: 1562-1569.
    CrossrefPubMedGoogle Scholar
  • 16 Katsuda S, Kaji T. Atherosclerosis and extracellular matrix. J Atheroscler Thromb 2003; 10: 267-274.
    CrossrefPubMedGoogle Scholar
  • 17 Siess W, Zangl KJ, Essler M. et al. Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions. Proc Natl Acad Sci USA 1999; 96: 6931-6936.
    CrossrefPubMedGoogle Scholar
  • 18 van Zanten GH, de Graaf S, Slootweg PJ. et al. Increased platelet deposition on atherosclerotic coronary arteries. J Clin Invest 1994; 93: 615-632.
    CrossrefPubMedGoogle Scholar
  • 19 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8: 1227-1234.
    CrossrefPubMedGoogle Scholar
  • 20 Jawien J, Nastalek P, Korbut R. Mouse models of experimental atherosclerosis. J Physiol Pharmacol 2004; 55: 503-517.
    PubMedGoogle Scholar
  • 21 Ni M, Chen WQ, Zhang Y. Animal models and potential mechanisms of plaque destabilisation and disruption. Heart 2009; 95: 1393-1398.
    CrossrefPubMedGoogle Scholar
  • 22 Reddick RL, Zhang SH, Maeda N. Aortic atherosclerotic plaque injury in apolipoprotein E deficient mice. Atherosclerosis 1998; 140: 297-305.
    CrossrefPubMedGoogle Scholar
  • 23 Kuijpers MJ, Gilio K, Reitsma S. et al. Complementary roles of platelets and coagulation in thrombus formation on plaques acutely ruptured by targeted ultrasound treatment: a novel intravital model. J Thromb Haemost 2009; 7: 152-161.
    CrossrefPubMedGoogle Scholar
  • 24 Gachet C, Cattaneo M, Ohlmann P. et al. Purinoceptors on blood platelets: further pharmacological and clinical evidence to suggest the presence of two ADP receptors. Br J Haematol 1995; 91: 434-444.
    CrossrefPubMedGoogle Scholar
  • 25 Nieswandt B, Schulte V, Bergmeier W. et al. Long-term antithrombotic protection by in vivo depletion of platelet glycoprotein VI in mice. J Exp Med 2001; 193: 459-469.
    CrossrefPubMedGoogle Scholar
  • 26 Carstairs KC. The identification of platelets and platelet antigens in histological sections. J Pathol Bacteriol 1965; 90: 225-231.
    CrossrefPubMedGoogle Scholar
  • 27 Perrault C, Mangin P, Santer M. et al. Role of the intracellular domains of GPIb in controlling the adhesive properties of the platelet GPIb/V/IX complex. Blood 2003; 101: 3477-3484.
    CrossrefPubMedGoogle Scholar
  • 28 Hagedorn I, Vogtle T, Nieswandt B. Arterial thrombus formation. Novel mechanisms and targets Novel mechanisms and targets. Hamostaseologie 2010; 30: 127-135.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Dubois C, Panicot-Dubois L, Merrill-Skoloff G. et al. Glycoprotein VI-dependent and -independent pathways of thrombus formation in vivo. Blood 2006; 107: 3902-3906.
    CrossrefPubMedGoogle Scholar
  • 30 Konstantinides S, Ware J, Marchese P. et al. Distinct antithrombotic consequences of platelet glycoprotein Ibalpha and VI deficiency in a mouse model of arterial thrombosis. J Thromb Haemost 2006; 4: 2014-2021.
    CrossrefPubMedGoogle Scholar
  • 31 Mangin P, Yap CL, Nonne C. et al. Thrombin overcomes the thrombosis defect associated with platelet GPVI/FcRgamma deficiency. Blood 2006; 107: 4346-4353.
    CrossrefPubMedGoogle Scholar
  • 32 Massberg S, Gawaz M, Gruner S. et al. A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo. J Exp Med 2003; 197: 41-49.
    CrossrefPubMedGoogle Scholar
  • 33 Eckly A, Hechler B, Freund M. et al. Mechanisms underlying FeCl3-induced arterial thrombosis. J Thromb Haemost. 2011 doi:10.1111/j.1538-7836.2011.04218.x.
    PubMedGoogle Scholar
  • 34 Rabie T, Varga-Szabo D, Bender M. et al. Diverging signaling events control the pathway of GPVI down-regulation in vivo. Blood 2007; 110: 529-535.
    CrossrefPubMedGoogle Scholar
  • 35 Eitzman DT, Westrick RJ, Xu Z. et al. Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery. Blood 2000; 96: 4212-4215.
    PubMedGoogle Scholar
  • 36 Eitzman DT, Westrick RJ, Xu Z. et al. Hyperlipidemia promotes thrombosis after injury to atherosclerotic vessels in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2000; 20: 1831-1834.
    CrossrefPubMedGoogle Scholar
  • 37 Westrick RJ, Bodary PF, Xu Z. et al. Deficiency of tissue factor pathway inhibitor promotes atherosclerosis and thrombosis in mice. Circulation 2001; 103: 3044-3046.
    CrossrefPubMedGoogle Scholar
  • 38 Toschi V, Gallo R, Lettino M. et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 1997; 95: 594-599.
    CrossrefPubMedGoogle Scholar
  • 39 Reininger AJ, Bernlochner I, Penz SM. et al. A 2-step mechanism of arterial thrombus formation induced by human atherosclerotic plaques. J Am Coll Cardiol 2010; 55: 1147-1158.
    CrossrefPubMedGoogle Scholar
  • 40 Libby P, Okamoto Y, Rocha VZ. et al. Inflammation in atherosclerosis: transition from theory to practice. Circ J 2010; 74: 213-220.
    CrossrefPubMedGoogle Scholar
  • 41 Hechler B, Lenain N, Marchese P. et al. A role of the fast ATP-gated P2X1 cation channel in thrombosis of small arteries in vivo. J Exp Med 2003; 198: 661-667.
    CrossrefPubMedGoogle Scholar
  • 42 Podrez EA, Byzova TV, Febbraio M. et al. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nat Med 2007; 13: 1086-1095.
    CrossrefPubMedGoogle Scholar
  • 43 Schaff M, Receveur N, Bourdon C. et al. Novel function of tenascin-C, a matrix protein relevant to atherosclerosis, in platelet recruitment and activation under flow. Arterioscler Thromb Vasc Biol 2011; 31: 117-124.
    CrossrefPubMedGoogle Scholar
  • 44 Eijgelaar WJ, Heeneman S, Daemen MJ. The vulnerable patient: refocusing on the plaque?. Thromb Haemost 2009; 102: 231-239.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Libby P. Molecular and cellular mechanisms of the thrombotic complications of atherosclerosis. J Lipid Res 2009; 50 Suppl S352-357.
    CrossrefPubMedGoogle Scholar
  • 46 Thim T, Hagensen MK, Bentzon JF. et al. From vulnerable plaque to atherothrombosis. J Int Med 2008; 263: 506-516.
    CrossrefPubMedGoogle Scholar
  • 47 Calara F, Silvestre M, Casanada F. et al. Spontaneous plaque rupture and secondary thrombosis in apolipoprotein E-deficient and LDL receptor-deficient mice. J Pathol 2001; 195: 257-263.
    CrossrefPubMedGoogle Scholar
  • 48 Jackson CL. Defining and defending murine models of plaque rupture. Arterioscler Thromb Vasc Biol 2007; 27: 973-977.
    CrossrefPubMedGoogle Scholar
  • 49 Johnson JL, Jackson CL. Atherosclerotic plaque rupture in the apolipoprotein E knockout mouse. Atherosclerosis 2001; 154: 399-406.
    CrossrefPubMedGoogle Scholar
  • 50 Schwartz SM, Galis ZS, Rosenfeld ME. et al. Plaque rupture in humans and mice. Arterioscler Thromb Vasc Biol 2007; 27: 705-713.
    CrossrefPubMedGoogle Scholar
  • 51 de Nooijer R, von der Thusen JH, Verkleij CJ. et al. Overexpression of IL-18 decreases intimal collagen content and promotes a vulnerable plaque phenotype in apolipoprotein-E-deficient mice. Arterioscler Thromb Vasc Biol 2004; 24: 2313-2319.
    CrossrefPubMedGoogle Scholar
  • 52 Gough PJ, Gomez IG, Wille PT. et al. Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice. J Clin Invest 2006; 116: 59-69.
    PubMedGoogle Scholar
  • 53 Zadelaar AS, von der Thusen JH, Boesten LS. et al. Increased vulnerability of pre-existing atherosclerosis in ApoE-deficient mice following adenovirus-mediated Fas ligand gene transfer. Atherosclerosis 2005; 183: 244-250.
    CrossrefPubMedGoogle Scholar
  • 54 von der Thusen JH, van Vlijmen BJ, Hoeben RC. et al. Induction of atherosclerotic plaque rupture in apolipoprotein E-/- mice after adenovirus-mediated transfer of p53. Circulation 2002; 105: 2064-2070.
    CrossrefPubMedGoogle Scholar