Format

Send to

Choose Destination
Nat Commun. 2018 Mar 14;9(1):1087. doi: 10.1038/s41467-018-03430-6.

Compression force sensing regulates integrin αIIbβ3 adhesive function on diabetic platelets.

Ju L1,2,3, McFadyen JD3, Al-Daher S3, Alwis I1,2,3, Chen Y1,4,5,6, Tønnesen LL1,2,3, Maiocchi S1,2, Coulter B1,2, Calkin AC3,7, Felner EI8, Cohen N9, Yuan Y1,2,3, Schoenwaelder SM1,2,3, Cooper ME10, Zhu C11,12,13, Jackson SP14,15,16,17.

Author information

1
Heart Research Institute, Thrombosis Group, Newtown, New South Wales, 2042, Australia.
2
Charles Perkins Centre, Level 3E Cardiovascular Division, The University of Sydney, New South Wales, 2006, Australia.
3
Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Victoria, 3004, Australia.
4
Coulter Department of Biomedical Engineering; and Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
5
Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
6
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, 92037, CA, USA.
7
Lipid Metabolism and Cardiometabolic Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia.
8
Division of Pediatric Endocrinology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
9
Clinical Diabetes, Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia.
10
Department of Diabetes, Central Clinical School, Monash University, Melbourne, 3004, Victoria, Australia.
11
Heart Research Institute, Thrombosis Group, Newtown, New South Wales, 2042, Australia. cheng.zhu@bme.gatech.edu.
12
Coulter Department of Biomedical Engineering; and Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA. cheng.zhu@bme.gatech.edu.
13
Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA. cheng.zhu@bme.gatech.edu.
14
Heart Research Institute, Thrombosis Group, Newtown, New South Wales, 2042, Australia. shaun.jackson@sydney.edu.au.
15
Charles Perkins Centre, Level 3E Cardiovascular Division, The University of Sydney, New South Wales, 2006, Australia. shaun.jackson@sydney.edu.au.
16
Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Victoria, 3004, Australia. shaun.jackson@sydney.edu.au.
17
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, 92037, CA, USA. shaun.jackson@sydney.edu.au.

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.

PMID:
29540687
PMCID:
PMC5852038
DOI:
10.1038/s41467-018-03430-6
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center