Abstract 17756: Platelet-derived Endothelial Cell Growth Factor Participates in Platelet Signaling and Promotes Thrombosis
Platelet-derived endothelial cell growth factor (PD-ECGF), also known as thymidine phosphorylase (TPase), is a dimeric protein highly expressed in platelets. PD-ECGF/TPase and its metabolite 2-deoxy-D-ribose-1-phosphate (dRP) play important roles in angiogenesis and dRP potentiates thrombin-induced platelet aggregation. Whether PD-ECGF/TPase directly affects platelet function is not known. By ex vivo studies of platelets treated with a pharmacologic PD-ECGF/TPase inhibitor KIN59, or platelets purified from mice with PD-ECGF/TPase deficiency we found that PD-ECGF/TPase participates in glycoprotein VI (GPVI) mediated signaling. Correspondingly, by using in vivo models of arterial thrombosis in genetically modified mice, we found that PD-ECGF/TPase plays an important role in platelet mediated thrombus formation. In response to ferric chloride injury, the time of blood flow cessation of carotid artery was significantly prolonged in tymp-/- and tymp+/- mice compared to wt mice. Bone marrow transplantation and platelet transfusion studies demonstrated that platelet PD-ECGF/TPase was responsible for the antithrombotic phenomenon found in the tymp deficient mice. PD-ECGF/TPase deficiency significantly attenuated ADP, thrombin and collagen stimulated P-selectin expression. Collagen or ADP induced platelet aggregation was also significantly retarded in tymp deficient platelets and in platelets exposed to the PD-ECGF/TPase inhibitor KIN59. PD-ECGF/TPase forms a complex with Lyn, Fyn and Yes kinases in both human and murine platelets. Collagen stimulation significantly decreased GPVI and Lyn association, but increased PD-ECGF/TPase and Lyn association; inhibition of PD-ECGF/TPase activity dramatically decreased PD-ECGF/TPase and Lyn association, but increased GPVI and Lyn association. Inhibition of PD-ECGF/TPase with KIN59 also significantly inhibited AKT phosphorylation. These data suggest that PD-ECGF/TPase regulates GPVI and Lyn association in platelets, and PD-ECGF/TPase enzymatic activity was essential. We conclude that PD-ECGF/TPase mediates platelet activation and targeting PD-ECGF/TP may be a novel anti-platelet and anti-thrombosis therapy.
- © 2013 by American Heart Association, Inc.