@article{5d84fe385027432fa52a2b13828e1e88,
title = "Compression force sensing regulates integrin αiIbβ3 adhesive function on diabetic platelets",
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.",
author = "Lining Ju and McFadyen, {James D.} and Saheb Al-Daher and Imala Alwis and Yunfeng Chen and T{\o}nnesen, {Lotte L.} and Sophie Maiocchi and Brianna Coulter and Calkin, {Anna C.} and Felner, {Eric I.} and Neale Cohen and Yuping Yuan and Schoenwaelder, {Simone M.} and Cooper, {Mark E.} and Cheng Zhu and Jackson, {Shaun P.}",
note = "Funding Information: We thank Miguel Cruz for reagents, along with Dr Fang Kong for assistance in the BFP instrumentation. We also thank Ms Jessica Maclean, Ms Katrina Ashworth, Dr Akiko Ono, Dr Roxane Darbousset, Dr Laura Norton, and Dr Mike CL Wu for technical assistance and helpful discussion. This work was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (APP1028564; APP1048574 - S.P.J.), the Australian Research Council (LE120100043 - S.P.J.), the National Institutes of Health/National Heart, Lung and Blood Institute, USA (HL132019 and CA214354 – C.Z.), the Royal College of Pathologists of Australasia Kanematsu research award, Diabetes Australia Research Trust grant G179720, Sydney Medical School early-career researcher kickstart grant—L.J. J.D.M was supported by a Wheaton Scholarship and CSL Behring Global Research Scholarship. S.A.-M was supported by Wheaton Scholarship. A.C.C. is a National Heart Foundation Future Leader Fellow (100067). S.P.J. is an NHMRC Senior Principal Research Fellow. L.J. is a National Heart Foundation of Australia postdoctoral fellow (101798). Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41467-018-03430-6",
language = "English (US)",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}