Compression force sensing regulates integrin α
adhesive function on diabetic platelets
, 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
, Simone M. Schoenwaelder
, Mark E. Cooper
, Cheng Zhu
Shaun P. Jackson
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 α
on discoid diabetic platelets, increasing its
association rate with immobilized ﬁbrinogen. This compressive force-induced integrin acti-
vation 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 α
adhesive function that leads to a distinct prothrombotic pheno-
type in diabetes.
Heart Research Institute, Thrombosis Group, Newtown, New South Wales 2042, Australia.
Charles Perkins Centre, Level 3E Cardiovascular Division, The
University of Sydney, New South Wales 2006, Australia.
Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne,
Victoria 3004, Australia.
Coulter Department of Biomedical Engineering; and Woodruff School of Mechanical Engineering, Georgia Institute of Technology,
Atlanta, GA 30332, USA.
Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla 92037 CA, USA.
Lipid Metabolism and Cardiometabolic
Disease Laboratory, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
Division of Pediatric Endocrinology, Emory University School
of Medicine, Atlanta, GA 30322, USA.
Clinical Diabetes, Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
Diabetes, Central Clinical School, Monash University, Melbourne 3004 Victoria, Australia. These authors contributed equally: Lining Ju, James D. McFadyen,
and Saheb Al-Daher. These authors jointly supervised this work: Cheng Zhu and Shaun P. Jackson. Correspondence and requests for materials should be
addressed to C.Z. (email: email@example.com) or to S.P.J. (email: firstname.lastname@example.org)