Journal
THROMBOSIS AND HAEMOSTASIS
Volume 117, Issue 8, Pages 1588-1600Publisher
SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN
DOI: 10.1160/TH16-12-0906
Keywords
Platelet glycoproteins; collagen receptors; signal transduction; thrombosis; fluid shear
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Funding
- British Heart Foundation [PG/14/47/30912, RG/09/003/27122]
- British Heart Foundation [RG/09/003/27122, PG/14/47/30912, RG/15/4/31268] Funding Source: researchfish
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The platelet receptors glycoprotein (Gp)VI, integrin 02131 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+](j) signals, but these varied in amplitude and temporal pattern alongside variable integrin activation. GpVI engagement produced large, sustained [Ca2+]; signals leading to real-time increases in integrins alpha(2)beta(1) and alpha(parallel to b)b(3)-mediated platelet adhesion. alpha(parallel to b)b(3)-dependent platelet aggregation was dependent on P2Y12 signalling. Co-engagement of alpha(2)beta(1) and GpIb/V/IX generated transient [Ca2+](i) spikes and low amplitude [Ca2+](i) responses that potentiated GpVI-dependent [Ca2+](i) signalling. Therefore alpha(2)beta(1), 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 alpha(parallel to b)b(3) in stable platelet adhesion and aggregation.
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