Activation of the murine EP3 receptor by low concentrations of PGE2 enhances platelet aggregation by inhibiting cAMP production, and EP3 deficiency protects against venous thrombosis in vivo.
Does activation of the EP3 receptor for PGE2 promote platelet aggregation and intravascular clot formation in a murine model?
The study identifies the EP3 receptor as the key mediator of PGE2-induced platelet aggregation at low concentrations, providing a mechanistic link between local inflammation and thrombosis.
p-value: p=<0.01
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 E2 (PGE2) on platelet aggregation varies significantly depending on its concentration. Low concentrations of PGE2 enhance platelet aggregation, whereas high PGE2 levels inhibit aggregation. The mechanism for this dual action of PGE2 is not clear. This study shows that among the four PGE2 receptors (EP1-EP4), activation of EP3 is sufficient to mediate the proaggregatory actions of low PGE2 concentration. In contrast, the prostacyclin receptor (IP) mediates the inhibitory effect of higher PGE2 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 PGE2 during an inflammatory process can modulate ensuing platelet responses.
Fabre et al. (Thu,) conducted a other in Platelet aggregation and thrombosis. Prostaglandin E2 (PGE2) and receptor deficiency vs. Wild-type platelets or vehicle was evaluated on Platelet aggregation and in vivo thrombus formation score (p=<0.01). Activation of the murine EP3 receptor by low concentrations of PGE2 enhances platelet aggregation by inhibiting cAMP production, and EP3 deficiency protects against venous thrombosis in vivo.