Elsevier

Cellular Signalling

Volume 27, Issue 1, January 2015, Pages 37-46
Cellular Signalling

SDF-1α is a novel autocrine activator of platelets operating through its receptor CXCR4

https://doi.org/10.1016/j.cellsig.2014.09.021Get rights and content
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Highlights

  • Collagen-induced platelet aggregation, TxA2 production and dense granule secretion require CXCR4 signalling.

  • CXCR4 regulates platelet thrombus formation.

  • SDF-1α-induced changes in cAMP and Ca(2 +) signalling require CXCR4.

  • SDF-1α, via CXCR4, enhances platelet activation responses to collagen, primarily through a TxA2-dependent and ADP-independent pathway.

Abstract

Platelets store and secrete the chemokine stromal cell-derived factor (SDF)-1α upon platelet activation, but the ability of platelet-derived SDF-1α to signal in an autocrine/paracrine manner mediating functional platelet responses relevant to thrombosis and haemostasis is unknown. We sought to explore the role of platelet-derived SDF-1α and its receptors, CXCR4 and CXCR7 in facilitating platelet activation and determine the mechanism facilitating SDF-1α-mediated regulation of platelet function. Using human washed platelets, CXCR4 inhibition, but not CXCR7 blockade significantly abrogated collagen-mediated platelet aggregation, dense granule secretion and thromboxane (Tx) A2 production. Time-dependent release of SDF-1α from collagen-activated platelets supports a functional role for SDF-1α in this regard. Using an in vitro whole blood perfusion assay, collagen-induced thrombus formation was substantially reduced with CXCR4 inhibition. In washed platelets, recombinant SDF-1α in the range of 20–100 ng/mL 1 could significantly enhance platelet aggregation responses to a threshold concentration of collagen. These enhancements were completely dependent on CXCR4, but not CXCR7, which triggered TxA2 production and dense granule secretion. Rises in cAMP were significantly blunted by SDF-1α, which could also enhance collagen-mediated Ca(2 +) mobilisation, both of which were mediated by CXCR4. This potentiating effect of SDF-1α primarily required TxA2 signalling acting upstream of dense granule secretion, whereas blockade of ADP signalling could only partially attenuate SDF-1α-induced platelet activation. Therefore, this study supports a potentially novel autocrine/paracrine role for platelet-derived SDF-1α during thrombosis and haemostasis, through a predominantly TxA2-dependent and ADP-independent pathway.

Abbreviations

SDF-1α
stromal cell-derived factor-1α
CXCR4
CXC chemokine receptor type 4
CXCR7
CXC chemokine receptor type 7
PRP
platelet-rich plasma
TxA2
thromboxane A2
GPCR
G-protein-coupled receptor
PGE1
prostaglandin E1
AR-C-66096
AR-C

Keywords

Platelet
Thrombosis
Signalling
Stromal cell-derived factor-1α
Thromboxane A2
Secretion

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