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 language | English |
|---|---|
| Article number | 1087 |
| Number of pages | 16 |
| Journal | Nature Communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Dec 2018 |
Cite this
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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 journal › Article › Research › peer-review
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
U2 - 10.1038/s41467-018-03430-6
DO - 10.1038/s41467-018-03430-6
M3 - Article
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1087
ER -