Compression force sensing regulates integrin αIIbβ3 adhesive function on diabetic platelets

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, Simone M. Schoenwaelder, Mark E. Cooper, Cheng Zhu () and Shaun P. Jackson ()
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Lining Ju: Heart Research Institute, Thrombosis Group, Newtown
James D. McFadyen: Monash University
Saheb Al-Daher: Monash University
Imala Alwis: Heart Research Institute, Thrombosis Group, Newtown
Yunfeng Chen: Heart Research Institute, Thrombosis Group, Newtown
Lotte L. Tønnesen: Heart Research Institute, Thrombosis Group, Newtown
Sophie Maiocchi: Heart Research Institute, Thrombosis Group, Newtown
Brianna Coulter: Heart Research Institute, Thrombosis Group, Newtown
Anna C. Calkin: Monash University
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
Simone M. Schoenwaelder: Heart Research Institute, Thrombosis Group, Newtown
Mark E. Cooper: Monash University
Cheng Zhu: Heart Research Institute, Thrombosis Group, Newtown
Shaun P. Jackson: Heart Research Institute, Thrombosis Group, Newtown

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03430-6

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