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Vascular wall-produced prostaglandin E2 exacerbates arterial thrombosis and atherothrombosis through platelet EP3 receptors.

Gross S, Tilly P, Hentsch D, Vonesch JL, Fabre JE - J. Exp. Med. (2007)

Bottom Line: 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 conclusion, PGE2 facilitates the initiation of arterial thrombosis and, hence, contributes to atherothrombosis.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT
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.

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Mouse atherosclerotic plaques produce functional PGE2. (A) PGE2 content of aortic arteries from ApoE+/+ versus ApoE−/− mice, showing that PGE2 tissue content is increased by the mere presence of atherosclerotic plaques, especially when the development of plaques was accelerated by a high fat diet for 3 wk. *, P < 0.05; ***, P < 0.001. HFD, high fat diet. (B) Representative traces and quantitative analysis showing Ep3+/+ versus Ep3−/− platelet aggregation in response to 0.5 mg/ml of mouse homogenized plaques. The lack of EP3 on platelets strikingly reduced their response to the plaque material, indicating that a molecule produced inside the plaques activates EP3. *, P = 0.002. (C) Representative traces and quantitative analysis of platelet aggregation induced by mouse homogenized plaques extracted from ApoE−/− mice treated by high doses of aspirin, documenting the lack of difference between Ep3+/+ versus Ep3−/− platelet responses when PGE2 production is depressed. Horizontal lines indicate the mean value in each group.
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fig4: Mouse atherosclerotic plaques produce functional PGE2. (A) PGE2 content of aortic arteries from ApoE+/+ versus ApoE−/− mice, showing that PGE2 tissue content is increased by the mere presence of atherosclerotic plaques, especially when the development of plaques was accelerated by a high fat diet for 3 wk. *, P < 0.05; ***, P < 0.001. HFD, high fat diet. (B) Representative traces and quantitative analysis showing Ep3+/+ versus Ep3−/− platelet aggregation in response to 0.5 mg/ml of mouse homogenized plaques. The lack of EP3 on platelets strikingly reduced their response to the plaque material, indicating that a molecule produced inside the plaques activates EP3. *, P = 0.002. (C) Representative traces and quantitative analysis of platelet aggregation induced by mouse homogenized plaques extracted from ApoE−/− mice treated by high doses of aspirin, documenting the lack of difference between Ep3+/+ versus Ep3−/− platelet responses when PGE2 production is depressed. Horizontal lines indicate the mean value in each group.

Mentions: To further substantiate its role in pathophysiological conditions, we examined whether PGE2 modulates thrombosis on atherosclerotic plaques. To confirm previous data that suggested the ability of plaque to produce PGE2 (8, 12), we quantified it directly in mouse plaques. ApoE+/+ aorta contained 661 ± 98 pg PGE2 (n = 12), whereas its amount in ApoE−/− aorta was found to be about fourfold higher, at 2,483 ± 485 pg (n = 14; P < 0.05). After we fed ApoE−/− mice a high fat diet, which is known to increase the size of atherosclerotic lesions, the difference was even more impressive (5,018 ± 705 pg/aorta; n = 23; P < 0.001; Fig. 4 A). Thus, atherosclerotic plaques produce PGE2.


Vascular wall-produced prostaglandin E2 exacerbates arterial thrombosis and atherothrombosis through platelet EP3 receptors.

Gross S, Tilly P, Hentsch D, Vonesch JL, Fabre JE - J. Exp. Med. (2007)

Mouse atherosclerotic plaques produce functional PGE2. (A) PGE2 content of aortic arteries from ApoE+/+ versus ApoE−/− mice, showing that PGE2 tissue content is increased by the mere presence of atherosclerotic plaques, especially when the development of plaques was accelerated by a high fat diet for 3 wk. *, P < 0.05; ***, P < 0.001. HFD, high fat diet. (B) Representative traces and quantitative analysis showing Ep3+/+ versus Ep3−/− platelet aggregation in response to 0.5 mg/ml of mouse homogenized plaques. The lack of EP3 on platelets strikingly reduced their response to the plaque material, indicating that a molecule produced inside the plaques activates EP3. *, P = 0.002. (C) Representative traces and quantitative analysis of platelet aggregation induced by mouse homogenized plaques extracted from ApoE−/− mice treated by high doses of aspirin, documenting the lack of difference between Ep3+/+ versus Ep3−/− platelet responses when PGE2 production is depressed. Horizontal lines indicate the mean value in each group.
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Related In: Results  -  Collection

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fig4: Mouse atherosclerotic plaques produce functional PGE2. (A) PGE2 content of aortic arteries from ApoE+/+ versus ApoE−/− mice, showing that PGE2 tissue content is increased by the mere presence of atherosclerotic plaques, especially when the development of plaques was accelerated by a high fat diet for 3 wk. *, P < 0.05; ***, P < 0.001. HFD, high fat diet. (B) Representative traces and quantitative analysis showing Ep3+/+ versus Ep3−/− platelet aggregation in response to 0.5 mg/ml of mouse homogenized plaques. The lack of EP3 on platelets strikingly reduced their response to the plaque material, indicating that a molecule produced inside the plaques activates EP3. *, P = 0.002. (C) Representative traces and quantitative analysis of platelet aggregation induced by mouse homogenized plaques extracted from ApoE−/− mice treated by high doses of aspirin, documenting the lack of difference between Ep3+/+ versus Ep3−/− platelet responses when PGE2 production is depressed. Horizontal lines indicate the mean value in each group.
Mentions: To further substantiate its role in pathophysiological conditions, we examined whether PGE2 modulates thrombosis on atherosclerotic plaques. To confirm previous data that suggested the ability of plaque to produce PGE2 (8, 12), we quantified it directly in mouse plaques. ApoE+/+ aorta contained 661 ± 98 pg PGE2 (n = 12), whereas its amount in ApoE−/− aorta was found to be about fourfold higher, at 2,483 ± 485 pg (n = 14; P < 0.05). After we fed ApoE−/− mice a high fat diet, which is known to increase the size of atherosclerotic lesions, the difference was even more impressive (5,018 ± 705 pg/aorta; n = 23; P < 0.001; Fig. 4 A). Thus, atherosclerotic plaques produce PGE2.

Bottom Line: 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 conclusion, PGE2 facilitates the initiation of arterial thrombosis and, hence, contributes to atherothrombosis.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus