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; Shaun P. Jackson

doi:10.1038/s41467-018-03430-6

Compression force sensing regulates integrin α_iIbβ₃ 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, Shaun P. Jackson

Research output: Contribution to journal › Article › peer-review

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 α_IIbβ₃ 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 α_IIbβ₃ adhesive function that leads to a distinct prothrombotic phenotype in diabetes.

Original language	English (US)
Article number	1087
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03430-6
State	Published - Dec 1 2018
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-018-03430-6

Cite this

Ju, L., McFadyen, J. D., Al-Daher, S., Alwis, I., Chen, Y., Tønnesen, L. L., Maiocchi, S., Coulter, B., Calkin, A. C., Felner, E. I., Cohen, N., Yuan, Y., Schoenwaelder, S. M., Cooper, M. E., Zhu, C., & Jackson, S. P. (2018). Compression force sensing regulates integrin α_iIbβ₃ adhesive function on diabetic platelets. Nature communications, 9(1), Article 1087. https://doi.org/10.1038/s41467-018-03430-6

Ju, L, McFadyen, JD, Al-Daher, S, Alwis, I, Chen, Y, Tønnesen, LL, Maiocchi, S, Coulter, B, Calkin, AC, Felner, EI, Cohen, N, Yuan, Y, Schoenwaelder, SM, Cooper, ME, Zhu, C & Jackson, SP 2018, 'Compression force sensing regulates integrin α_iIbβ₃ adhesive function on diabetic platelets', Nature communications, vol. 9, no. 1, 1087. https://doi.org/10.1038/s41467-018-03430-6

@article{4e7b2cd929bc49a6b82894cf9892a827,

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 = "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 Research",

number = "1",

}

TY - JOUR

T1 - Compression force sensing regulates integrin αiIbβ3 adhesive function on diabetic platelets

AU - Ju, Lining

AU - McFadyen, James D.

AU - Al-Daher, Saheb

AU - Alwis, Imala

AU - Chen, Yunfeng

AU - Tønnesen, Lotte L.

AU - Maiocchi, Sophie

AU - Coulter, Brianna

AU - Calkin, Anna C.

AU - Felner, Eric I.

AU - Cohen, Neale

AU - Yuan, Yuping

AU - Schoenwaelder, Simone M.

AU - Cooper, Mark E.

AU - Zhu, Cheng

AU - Jackson, Shaun P.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85044220036&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044220036&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-03430-6

DO - 10.1038/s41467-018-03430-6

M3 - Article

C2 - 29540687

AN - SCOPUS:85044220036

SN - 2041-1723

VL - 9

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 1087

ER -

Compression force sensing regulates integrin α_iIbβ₃ adhesive function on diabetic platelets

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this