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

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 Ca2+ 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.

• Authors: Tony G Walsh, Matthew T Harper, Alastair W Poole
• Journal: Cellular signalling (Cell Signal) Vol. 27 Issue 1 Pg. 37-46 (Jan 2015) ISSN: 1873-3913 [Electronic] England
• PMID: 25283599 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier Inc.

Chemical References

• Chemokine CXCL12
• Receptors, CXCR4
• Thromboxane A2
• Adenosine Diphosphate
• Collagen
• Cyclic AMP

Topics

• Adenosine Diphosphate (pharmacology)
• Animals
• Autocrine Communication (drug effects)
• Blood Platelets (drug effects, metabolism)
• Calcium Signaling (drug effects)
• Chemokine CXCL12 (pharmacology)
• Collagen (pharmacology)
• Cyclic AMP (metabolism)
• Horses
• Humans
• Platelet Activation (drug effects)
• Platelet Aggregation (drug effects)
• Receptors, CXCR4 (metabolism)
• Thrombosis (metabolism, pathology)
• Thromboxane A2 (biosynthesis)