Vascular wall-produced prostaglandin E2 exacerbates arterial thrombosis and atherothrombosis through platelet EP3 receptors.
Prostanoids, bioactive lipids derived from arachidonic acid (AA), are important for vascular homeostasis. Among them, prostaglandin E2 (PGE2) enhances aggregation of platelets submaximally stimulated in vitro. This results from activation of EP3, one of the four PGE2 receptors, which decreases the threshold at which agonists activate platelets to aggregate. Although PGE2 altered venous thrombosis induced by administration of AA, its role in pathophysiopathological conditions has remained speculative. We report that arterial walls subjected to inflammatory stimuli produce PGE2. In several models, we show that PGE2 produced by the arterial wall facilitates arterial thrombosis. Next, we detected PGE2 in mouse atherosclerotic plaques. We demonstrate that this plaque-produced PGE2 is not altered and is still able to activate EP3. In addition, we present evidence that PGE2 can leave the plaque and activate EP3 on blood platelets. Consistent with these findings, we observed that atherothrombosis induced in vivo by mechanical rupture of the plaque was drastically decreased when platelets lacked EP3. In conclusion, PGE2 facilitates the initiation of arterial thrombosis and, hence, contributes to atherothrombosis. Inhibition of the platelet EP3 receptor should improve prevention of atherothrombosis.
Gross
Sabrina
S
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U596, Centre National de la Recherche Scientifique UMR7104, Université Louis Pasteur, 67400 Illkirch, France.
Tilly
Peggy
P
Hentsch
Didier
D
Vonesch
Jean-Luc
JL
Fabre
Jean-Etienne
JE
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D016718:Arachidonic Acid / Q000633:toxicity; D001158:Arteries / Q000276:immunology* / Q000378:metabolism; D050197:Atherosclerosis / Q000276:immunology* / Q000503:physiopathology; D001792:Blood Platelets / Q000378:metabolism*; D002341:Carotid Artery Thrombosis / Q000139:chemically induced / Q000503:physiopathology*; D015232:Dinoprostone / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D051379:Mice; D018345:Mice, Knockout; D010974:Platelet Aggregation / Q000276:immunology; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D018709:Statistics, Nonparametric
D001057:Apolipoproteins E; C545648:Ptger3 protein, mouse; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D016718:Arachidonic Acid; D015232:Dinoprostone