title: 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.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom.
authors.forename: Tony G
authors.initials: TG
authors.lastname: Walsh
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Harper
authors.affiliation: School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom. Electronic address: A.Poole@bristol.ac.uk.
authors.forename: Alastair W
authors.initials: AW
authors.lastname: Poole
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006736:Horses; D006801:Humans; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000378:metabolism*; D013927:Thrombosis / Q000378:metabolism / Q000473:pathology; D013928:Thromboxane A2 / Q000096:biosynthesis
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D003094:Collagen; D000242:Cyclic AMP
keywords: Platelet; Secretion; Signalling; Stromal cell-derived factor-1α; Thrombosis; Thromboxane A(2)