Differential integrin activity mediated by platelet collagen receptor engagement under flow conditions

Pugh, Nicholas and Maddox, Ben D. and Bihan, Dominique and Taylor, Kirk A. and Mahaut-Smith, Martyn P. and Farndale, Richard W. (2017) Differential integrin activity mediated by platelet collagen receptor engagement under flow conditions. Thrombosis and Haemostasis, 117 (8). pp. 1588-1600. ISSN 0340-6245

[img]
Preview
Text
Published Version
Available under the following license: Creative Commons Attribution Non-commercial No Derivatives.

Download (1MB) | Preview
Official URL: https://doi.org/10.1160/TH16-12-0906

Abstract

The platelet receptors glycoprotein (Gp)VI, integrin α2β1 and GpIb/V/IX mediate platelet adhesion and activation during thrombogenesis. Increases of intracellular Ca2+ ([Ca2+]i) are key signals during platelet activation; however, their relative importance in coupling different collagen receptors to functional responses under shear conditions remains unclear. To study shear-dependent, receptor-specific platelet responses, we used collagen or combinations of receptor-specific collagen-mimetic peptides as substrates for platelet adhesion and activation in whole human blood under arterial flow conditions and compared real-time and endpoint parameters of thrombus formation alongside [Ca2+]i measurements using confocal imaging. All three collagen receptors coupled to [Ca2+]i signals, but these varied in amplitude and temporal pattern alongside variable integrin activation. GpVI engagement produced large, sustained [Ca2+]i signals leading to realtime increases in integrins α2β1− and αIIbβ3-mediated platelet adhesion. αIIbβ3-dependent platelet aggregation was dependent on P2Y12 signalling. Co-engagement of α2β1 and GpIb/V/IX generated transient [Ca2+]i spikes and low amplitude [Ca2+]i responses that potentiated GpVI-dependent [Ca2+]i signalling. Therefore α2β1 GpIb/V/IX and GpVI synergise to generate [Ca2+]i signals that regulate platelet behaviour and thrombus formation. Antagonism of secondary signalling pathways reveals distinct, separate roles for αIIbβ3 in stable platelet adhesion and aggregation.

Item Type: Journal Article
Keywords: Platelet glycoproteins, collagen receptors, signal transduction, thrombosis, fluid shear
Faculty: ARCHIVED Faculty of Science & Technology (until September 2018)
Depositing User: Dr Nicholas Pugh
Date Deposited: 06 Jun 2017 10:17
Last Modified: 28 Nov 2018 12:10
URI: http://arro.anglia.ac.uk/id/eprint/701786

Actions (login required)

Edit Item Edit Item