Compression force sensing regulates integrin αIIbβ3 adhesive function on diabetic platelets

• DOI: 10.1038/s41467-018-03430-6
• Publication Date: 2018-03-08T22:05:04Z
• Authors: 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. Schoenw...; Mark E. Cooper; Cheng Zhu; Shaun P. Jackson
• Keywords: Adult; Blood Platelets; Male; 0301 basic medicine; Ticlopidine; 1300 Biochemistry; Platelet Aggregation; Science; 610; General Physics and Astronomy; Genetics and Molecular Biology; Platelet Glycoprotein GPIIb-IIIa Complex; Article; Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Platelet Adhesiveness; Animals; Humans; 3100 Physics and Astronomy; Aspirin; Q; Thrombosis; General Chemistry; Middle Aged; 1600 Chemistry; Clopidogrel; Mice, Inbred C57BL; Diabetes Mellitus, Type 1; General Biochemistry; Female

AbstractDiabetes 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.