Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation
Jean-Etienne Fabre, … , Thomas M. Coffman, Beverly H. Koller
Jean-Etienne Fabre, … , Thomas M. Coffman, Beverly H. Koller
Published March 1, 2001
Citation Information: J Clin Invest. 2001;107(5):603-610. https://doi.org/10.1172/JCI10881.
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Article

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

Abstract

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.

Authors

Jean-Etienne Fabre, MyTrang Nguyen, Krairek Athirakul, Kenneth Coggins, John D. McNeish, Sandra Austin, Leslie K. Parise, Garret A. FitzGerald, Thomas M. Coffman, Beverly H. Koller

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The PGE2-induced inhibition of aggregation is mediated by the IP recepto...
The PGE2-induced inhibition of aggregation is mediated by the IP receptor. (a) PGE2 (10–4 M) alone is sufficient to induce aggregation of IP-deficient platelets, but not wild-type platelets. Further aggregation observed upon addition of ADP reveals that the response to PGE2 in IP-deficient platelets is submaximal. (b) PGE2 (10–4 M) induced aggregation of IP-deficient platelets. The failure to observe aggregation of platelets deficient in both the IP and the TP receptors under similar conditions suggests that high concentrations of PGE2 induced aggregation through the TP receptor. (c) PGE2 (6 × 10–4 M) fails to abolish ADP (5 μM) induced aggregation in platelets lacking both the IP and TP receptors. (d) Comparison of aggregation induced by 5 μM ADP in the presence and absence of 6 × 10–4M PGE2, in platelets deficient in each of the EP receptors. Bars = 1 minute. Three experiments were carried out, and representative traces from these experiments are shown. Differences observed on comparison of the mean maximal aggregation for the various genotypes (a–c) or between PGE2-treated and untreated samples (d) are significant (P < 0.01; unpaired t test).