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Compression force sensing regulates integrin αIIbβ3 adhesive function on diabetic platelets

Author

Listed:
  • Lining Ju

    (Heart Research Institute, Thrombosis Group, Newtown
    The University of Sydney
    Monash University)

  • James D. McFadyen

    (Monash University)

  • Saheb Al-Daher

    (Monash University)

  • Imala Alwis

    (Heart Research Institute, Thrombosis Group, Newtown
    The University of Sydney
    Monash University)

  • Yunfeng Chen

    (Heart Research Institute, Thrombosis Group, Newtown
    Georgia Institute of Technology
    Georgia Institute of Technology
    The Scripps Research Institute)

  • Lotte L. Tønnesen

    (Heart Research Institute, Thrombosis Group, Newtown
    The University of Sydney
    Monash University)

  • Sophie Maiocchi

    (Heart Research Institute, Thrombosis Group, Newtown
    The University of Sydney)

  • Brianna Coulter

    (Heart Research Institute, Thrombosis Group, Newtown
    The University of Sydney)

  • Anna C. Calkin

    (Monash University
    Baker Heart and Diabetes Institute, Melbourne)

  • Eric I. Felner

    (Emory University School of Medicine)

  • Neale Cohen

    (Clinical Diabetes, Baker Heart and Diabetes Institute)

  • Yuping Yuan

    (Heart Research Institute, Thrombosis Group, Newtown
    The University of Sydney
    Monash University)

  • Simone M. Schoenwaelder

    (Heart Research Institute, Thrombosis Group, Newtown
    The University of Sydney
    Monash University)

  • Mark E. Cooper

    (Monash University)

  • Cheng Zhu

    (Heart Research Institute, Thrombosis Group, Newtown
    Georgia Institute of Technology
    Georgia Institute of Technology)

  • Shaun P. Jackson

    (Heart Research Institute, Thrombosis Group, Newtown
    The University of Sydney
    Monash University
    The Scripps Research Institute)

Abstract

Diabetes is associated with an exaggerated platelet thrombotic response at sites of vascular injury. Biomechanical forces regulate platelet activation, although the impact of diabetes on this process remains ill-defined. Using a biomembrane force probe (BFP), we demonstrate that compressive force activates integrin αIIbβ3 on discoid diabetic platelets, increasing its association rate with immobilized fibrinogen. This compressive force-induced integrin activation is calcium and PI 3-kinase dependent, resulting in enhanced integrin affinity maturation and exaggerated shear-dependent platelet adhesion. Analysis of discoid platelet aggregation in the mesenteric circulation of mice confirmed that diabetes leads to a marked enhancement in the formation and stability of discoid platelet aggregates, via a mechanism that is not inhibited by therapeutic doses of aspirin and clopidogrel, but is eliminated by PI 3-kinase inhibition. These studies demonstrate the existence of a compression force sensing mechanism linked to αIIbβ3 adhesive function that leads to a distinct prothrombotic phenotype in diabetes.

Suggested Citation

  • Lining Ju & James D. McFadyen & Saheb Al-Daher & Imala Alwis & Yunfeng Chen & Lotte L. Tønnesen & Sophie Maiocchi & Brianna Coulter & Anna C. Calkin & Eric I. Felner & Neale Cohen & Yuping Yuan & Simo, 2018. "Compression force sensing regulates integrin αIIbβ3 adhesive function on diabetic platelets," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03430-6
    DOI: 10.1038/s41467-018-03430-6
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