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(Circulation. 2001;104:1176.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Increased Bleeding Tendency and Decreased Susceptibility to Thromboembolism in Mice Lacking the Prostaglandin E Receptor Subtype EP₃

Hong Ma, MD; Akiyoshi Hara, PhD; Chun- Yang Xiao, PhD; Yuji Okada, MD; Osamu Takahata, MD; Kazuhiro Nakaya, PhD; Yukihiko Sugimoto, MD; Atsushi Ichikawa, MD; Shuh Narumiya, MD; Fumitaka Ushikubi, MD

From the Department of Pharmacology (H.M., A.H., C.-Y.X., Y.O., O.T., K.N., F.U.), Asahikawa Medical College, Asahikawa, and the Department of Physiological Chemistry (Y.S., A.I.), Faculty of Pharmaceutical Sciences, and Department of Pharmacology (S.N.), Faculty of Medicine, Kyoto University, Kyoto, Japan.

Correspondence to Fumitaka Ushikubi, Department of Pharmacology, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa 078-8510, Japan. E-mail ushikubi{at}asahikawa-med.ac.jp

Background—— Among the prostanoids, thromboxane (TX) A₂ is a potent stimulator of platelets, whereas prostaglandin (PG) I₂ inhibits their activation. The roles of PGE₂ in the regulation of platelet function have not been established, however, and the contribution of PGE₂ in hemostasis and thromboembolism is poorly understood. The present study was intended to clarify these roles of PGE₂ by using mice lacking the PGE₂ receptor subtype 3 (EP₃^-/- mice).

Methods and Results—— Expression of mRNAs for EP₃ in murine platelets was confirmed by quantitative reverse transcription-polymerase chain reaction. PGE₂ and AE-248, a selective EP₃ agonist, showed concentration-dependent potentiation of platelet aggregation induced by U46619, a TXA₂ receptor agonist, although PGE₂ alone could not induce aggregation. PGE₂ and AE-248 increased cytosolic calcium ion concentration ([Ca²⁺]_i), and AE-248 inhibited the forskolin-induced increase in cytosolic cAMP concentration ([cAMP]_i), suggesting G_i coupling of EP₃. The potentiating effects of PGE₂ and AE-248 on platelet aggregation along with their effects on [Ca²⁺]_i and [cAMP]_i were absent in EP₃^-/- mice. In vivo, the bleeding time was significantly prolonged in EP₃^-/- mice. Moreover, when mice were challenged intravenously with arachidonic acid, mortality and thrombus formation in the lung were significantly reduced in EP₃^-/- mice.

Conclusions—— PGE₂ potentiated platelet aggregation induced by U46619 via EP₃ by increasing [Ca²⁺]_i, decreasing [cAMP]_i, or both. This potentiating action of PGE₂ via EP₃ is essential in mediating both physiological and pathological effects of PGE₂ in vivo.

Key Words: platelets • prostaglandins • thromboxane • hemorrhage • thrombosis

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