Sphingosine-1-phosphate regulates platelet fibrinogen binding via sphingosine-1-phosphate receptor type 4.

BACKGROUND

Sphingosine-1-phosphate (S1P) is a bioactive signaling sphingolipid secreted by platelets during activation. Platelets express distinct S1P receptors on their surface, and a comprehensive understanding of their effects is yet to be achieved.

OBJECTIVES

Here, we describe the regulation of fibrinogen binding in activated platelets via S1P receptor type 4 (S1PR4).

METHODS

Thrombus formation and platelet function on an S1PR4-deficient (S1pr4-/-) background were assessed in an ex vivo flow chamber setting and by rotational thromboelastometry. In vivo coagulation was studied in a murine model of polymicrobial abdominal sepsis. Fibrinogen binding was assessed by flow cytometry in the murine and human systems.

RESULTS

In the colon ascendens stent peritonitis model, an increased incidence of disseminated intravascular coagulation was observed in S1pr4-/- mice. Murine platelets from S1pr4-/- mice showed excessive fibrinogen binding and disorganized thrombus formation compared with wild-type platelets. Rotational thromboelastometry confirmed these results, showing a reduced clotting time and an increased clot size in S1pr4-/- mice. Flow cytometry analysis of glycoprotein IIb/IIIa expression indicated an increased low-to-high-affinity switch for increased fibrinogen binding in S1pr4-/- platelets. Analysis of human platelets using a specific antagonist showed that S1PR4 signaling impacted fibrinogen binding.

CONCLUSION

These findings strongly suggest that S1P signaling via S1PR4 acts as a negative regulator of fibrinogen binding in activated platelets.