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

Research output: Contribution to journalArticleResearchpeer-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 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.

Original languageEnglish
Article number1087
Number of pages16
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018

Cite this

Ju, Lining ; McFadyen, James D. ; Al-Daher, Saheb ; Alwis, Imala ; Chen, Yunfeng ; Tønnesen, Lotte L. ; Maiocchi, Sophie ; Coulter, Brianna ; Calkin, Anna C. ; Felner, Eric I. ; Cohen, Neale ; Yuan, Yuping ; Schoenwaelder, Simone M. ; Cooper, Mark E. ; Zhu, Cheng ; Jackson, Shaun P. / Compression force sensing regulates integrin αiIbβ3 adhesive function on diabetic platelets. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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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.}",
year = "2018",
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doi = "10.1038/s41467-018-03430-6",
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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 αiIbβ3 adhesive function on diabetic platelets' Nature Communications, vol. 9, no. 1, 1087. https://doi.org/10.1038/s41467-018-03430-6

Compression force sensing regulates integrin αiIbβ3 adhesive function on diabetic platelets. / Ju, Lining; McFadyen, James D.; Al-Daher, Saheb; Alwis, Imala; Chen, Yunfeng; Tønnesen, Lotte L.; Maiocchi, Sophie; Coulter, Brianna; Calkin, Anna C.; Felner, Eric I.; Cohen, Neale; Yuan, Yuping; Schoenwaelder, Simone M.; Cooper, Mark E.; Zhu, Cheng; Jackson, Shaun P.

In: Nature Communications, Vol. 9, No. 1, 1087, 01.12.2018.

Research output: Contribution to journalArticleResearchpeer-review

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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.

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