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Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E

Nature Medicine volume 9, pages 61–67 (2003)Cite this article

Abstract

We studied whether circulating activated platelets and platelet–leukocyte aggregates cause the development of atherosclerotic lesions in apolipoprotein-E–deficient (Apoe−/−) mice. Circulating activated platelets bound to leukocytes, preferentially monocytes, to form platelet–monocyte/leukocyte aggregates. Activated platelets and platelet–leukocyte aggregates interacted with atherosclerotic lesions. The interactions of activated platelets with monocytes and atherosclerotic arteries led to delivery of the platelet-derived chemokines CCL5 (regulated on activation, normal T cell expressed and secreted, RANTES) and CXCL4 (platelet factor 4) to the monocyte surface and endothelium of atherosclerotic arteries. The presence of activated platelets promoted leukocyte binding of vascular cell adhesion molecule-1 (VCAM-1) and increased their adhesiveness to inflamed or atherosclerotic endothelium. Injection of activated wild-type, but not P-selectin–deficient, platelets increased monocyte arrest on the surface of atherosclerotic lesions and the size of atherosclerotic lesions in Apoe−/− mice. Our results indicate that circulating activated platelets and platelet–leukocyte/monocyte aggregates promote formation of atherosclerotic lesions. This role of activated platelets in atherosclerosis is attributed to platelet P-selectin–mediated delivery of platelet-derived proinflammatory factors to monocytes/leukocytes and the vessel wall.

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Figure 1: Interactions of activated platelets with leukocytes in vivo.
Figure 2: Interactions of activated platelets with atherosclerotic arteries.
Figure 3: Deposition of platelet-derived proinflammatory factors on atherosclerotic endothelium.
Figure 4: Deposition of platelet-derived proinflammatory mediators on the surface of monocytes.
Figure 5: Monocyte/leukocyte–endothelial interactions in the presence of activated platelets.
Figure 6: Repeated injections of wild-type but not Selp−/− activated platelets or the supernatant of activated wild-type platelets exacerbate atherosclerosis in Apoe−/− mice.

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Acknowledgements

We thank M. Kirkpatrick for mouse husbandry; A.L. Beaudet for Selp−/− mice; R.P. McEver for P-selectin mAbs; D.D. Wagner and H. Ni for advice on murine platelet isolation; and J.A. Redick for technical assistance in scanning electron microscopy and confocal microscopy. This work was supported by NIH grant HL-58108 to K.L., by DFG grant We-1913/2 to C.W. and AHA post-doctoral fellowship award 0120404U to Y.H.

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Authors and Affiliations

  1. Department of Biomedical Engineering and Cardiovascular Research Center, University of Virginia, Health Science Center, Charlottesville, Virginia, USA

    Yuqing Huo, S. Bradley Forlow, David F. Smith, Matthew Craig Hyman & Klaus Ley

  2. Department of Molecular Cardiovascular Research, University Hospital Aachen, Aachen, Germany

    Andreas Schober & Christian Weber

  3. Skirball Institute of Biomolecular Medicine, New York, New York, USA

    Steffen Jung

  4. Howard Hughes Medical Institute, New York, New York, USA

    Dan R. Littman

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Correspondence to Klaus Ley.

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Huo, Y., Schober, A., Forlow, S. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 9, 61–67 (2003). https://doi.org/10.1038/nm810

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