Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation

The importance of arachidonic acid metabolites (termed eicosanoids), particularly those derived from the COX-1 and COX-2 pathways (termed prostanoids), in platelet homeostasis has long been recognized, Thromboxane is a potent agonist, whereas prostacyclin is an inhibitor of platelet aggregation. In contrast, the effect of prostaglandin E-2 (PGE(2)) on platelet aggregation varies significantly depending on its concentration. Low concentrations of PGE(2) enhance platelet aggregation, whereas high PGE(2) levels inhibit aggregation. The mechanism for this dual action of PGE(2) is not clear. This study shows that among the four PGE(2) receptors (EP1-EP4), activation of EP3 is sufficient to mediate the proaggregatory actions of low PGE(2) concentration. In contrast, the prostacyclin receptor (IP) mediates the inhibitory effect of higher PGE(2) concentrations. Furthermore, the relative activation of these two receptors, EP3 and IP, regulates the intracellular level of cAMP and in this way conditions the response of the platelet to aggregating agents. Consistent with these findings, loss of the EP3 receptor in a model of venous inflammation protects against formation of intravascular clots. Our results suggest that local production of PGE(2) during an inflammatory process can modulate ensuing platelet responses.