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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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The in vitro facilitating effect of PGE2 is not induced by activated platelets. (A) Representative traces of aggregation of WT (green traces) versus EP3-deficient (red traces) platelets activated by 1.5 or 2 μg/ml of collagen. These doses were chosen to induce partial and submaximal aggregation, respectively, to ensure that any potentiation could be evidenced. The increase in light transmission indicates an increase in the aggregation of platelets. (B) Quantitative analysis showing that the maximal aggregation of platelets was not altered by absence of the EP3 receptor to PGE2. Horizontal lines indicate the mean value for each group.
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fig2: The in vitro facilitating effect of PGE2 is not induced by activated platelets. (A) Representative traces of aggregation of WT (green traces) versus EP3-deficient (red traces) platelets activated by 1.5 or 2 μg/ml of collagen. These doses were chosen to induce partial and submaximal aggregation, respectively, to ensure that any potentiation could be evidenced. The increase in light transmission indicates an increase in the aggregation of platelets. (B) Quantitative analysis showing that the maximal aggregation of platelets was not altered by absence of the EP3 receptor to PGE2. Horizontal lines indicate the mean value for each group.

Mentions: PGE2 facilitates thrombosis by decreasing the activation threshold of platelets, making them more sensitive to their agonists (14). In vivo, PGE2 is produced by the arterial wall, but perhaps also by activated platelets themselves (20). In the latter case, PGE2 might facilitate the effect of ADP and TXA2 secreted by activated platelets to recruit more platelets. This would suggest that PGE2 plays a role in thrombosis amplification rather than in thrombosis driven by inflammation of the vascular wall. To address this possibility, we examined whether in vitro aggregation of isolated platelets is EP3 dependent. Platelets stimulated with low concentrations of collagen elicited partial aggregation that was not modified by the presence or the absence of EP3 (47.6 ± 2.1% vs. 47.9 ± 4.2% [n = 4] at 1.5 μg/ml collagen [P = 0.95] and 58.8 ± 4.2% vs. 57.2 ± 3% [n = 9] at 2 μg/ml collagen [P = 0.75], respectively; Fig. 2). The absence of potentiation shows that activated platelets do not produce enough PGE2 to amplify aggregation in vitro.


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)

The in vitro facilitating effect of PGE2 is not induced by activated platelets. (A) Representative traces of aggregation of WT (green traces) versus EP3-deficient (red traces) platelets activated by 1.5 or 2 μg/ml of collagen. These doses were chosen to induce partial and submaximal aggregation, respectively, to ensure that any potentiation could be evidenced. The increase in light transmission indicates an increase in the aggregation of platelets. (B) Quantitative analysis showing that the maximal aggregation of platelets was not altered by absence of the EP3 receptor to PGE2. Horizontal lines indicate the mean value for each group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2118736&req=5

fig2: The in vitro facilitating effect of PGE2 is not induced by activated platelets. (A) Representative traces of aggregation of WT (green traces) versus EP3-deficient (red traces) platelets activated by 1.5 or 2 μg/ml of collagen. These doses were chosen to induce partial and submaximal aggregation, respectively, to ensure that any potentiation could be evidenced. The increase in light transmission indicates an increase in the aggregation of platelets. (B) Quantitative analysis showing that the maximal aggregation of platelets was not altered by absence of the EP3 receptor to PGE2. Horizontal lines indicate the mean value for each group.
Mentions: PGE2 facilitates thrombosis by decreasing the activation threshold of platelets, making them more sensitive to their agonists (14). In vivo, PGE2 is produced by the arterial wall, but perhaps also by activated platelets themselves (20). In the latter case, PGE2 might facilitate the effect of ADP and TXA2 secreted by activated platelets to recruit more platelets. This would suggest that PGE2 plays a role in thrombosis amplification rather than in thrombosis driven by inflammation of the vascular wall. To address this possibility, we examined whether in vitro aggregation of isolated platelets is EP3 dependent. Platelets stimulated with low concentrations of collagen elicited partial aggregation that was not modified by the presence or the absence of EP3 (47.6 ± 2.1% vs. 47.9 ± 4.2% [n = 4] at 1.5 μg/ml collagen [P = 0.95] and 58.8 ± 4.2% vs. 57.2 ± 3% [n = 9] at 2 μg/ml collagen [P = 0.75], respectively; Fig. 2). The absence of potentiation shows that activated platelets do not produce enough PGE2 to amplify aggregation in vitro.

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