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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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Related in: MedlinePlus

Proposed model for in vivo action of PGE2/EP3 upon thrombosis. Platelet agonists activate their specific receptor (R), triggering the signaling cascade and exposing the integrin αIIbβ3, which is crucial for platelet aggregation. Inflammation of the vessel or rupture of the plaque releases PGE2 locally. Activation of its EP3 receptor on platelets decreases the internal level of cAMP, whereas activation of IP receptor by endothelium-produced PGI2 increases it. This balance between PGE2 and PGI2 eventually determines the intracellular level of cAMP. Because the cAMP level inhibits some steps of the signaling cascade activated by R, the balance ultimately regulates the platelet capability to aggregate in response to its agonists. Hence, platelet rupture or vessel wall inflammation enhances platelet aggregability via the release of PGE2.
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fig7: Proposed model for in vivo action of PGE2/EP3 upon thrombosis. Platelet agonists activate their specific receptor (R), triggering the signaling cascade and exposing the integrin αIIbβ3, which is crucial for platelet aggregation. Inflammation of the vessel or rupture of the plaque releases PGE2 locally. Activation of its EP3 receptor on platelets decreases the internal level of cAMP, whereas activation of IP receptor by endothelium-produced PGI2 increases it. This balance between PGE2 and PGI2 eventually determines the intracellular level of cAMP. Because the cAMP level inhibits some steps of the signaling cascade activated by R, the balance ultimately regulates the platelet capability to aggregate in response to its agonists. Hence, platelet rupture or vessel wall inflammation enhances platelet aggregability via the release of PGE2.

Mentions: PGE2 appears in our study as a molecule playing a role in vascular wall homeostasis through its action in limited healing thrombosis. Indeed, the fact that PGE2 facilitated thrombosis in the arterial flow in response to inflammation indicates that its in vivo effect is sufficient to oppose PGI2. Therefore, even when a small vascular lesion releases or exposes low amounts of agonists, the concentrations of which are below the platelet activation threshold, the presence of PGE2 produced by local inflammation may sensitize platelets and foster healing thrombosis. Conversely, PGI2 produced upon inflammation by neighboring functional endothelial cells limits the extent of thrombosis (32) to restrict it to the lesion. Hence, PGE2 catalyzes healing thrombosis on small lesions, whereas PGI2 restricts its amplification to keep it focalized (Fig. 7).


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)

Proposed model for in vivo action of PGE2/EP3 upon thrombosis. Platelet agonists activate their specific receptor (R), triggering the signaling cascade and exposing the integrin αIIbβ3, which is crucial for platelet aggregation. Inflammation of the vessel or rupture of the plaque releases PGE2 locally. Activation of its EP3 receptor on platelets decreases the internal level of cAMP, whereas activation of IP receptor by endothelium-produced PGI2 increases it. This balance between PGE2 and PGI2 eventually determines the intracellular level of cAMP. Because the cAMP level inhibits some steps of the signaling cascade activated by R, the balance ultimately regulates the platelet capability to aggregate in response to its agonists. Hence, platelet rupture or vessel wall inflammation enhances platelet aggregability via the release of PGE2.
© Copyright Policy
Related In: Results  -  Collection

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

fig7: Proposed model for in vivo action of PGE2/EP3 upon thrombosis. Platelet agonists activate their specific receptor (R), triggering the signaling cascade and exposing the integrin αIIbβ3, which is crucial for platelet aggregation. Inflammation of the vessel or rupture of the plaque releases PGE2 locally. Activation of its EP3 receptor on platelets decreases the internal level of cAMP, whereas activation of IP receptor by endothelium-produced PGI2 increases it. This balance between PGE2 and PGI2 eventually determines the intracellular level of cAMP. Because the cAMP level inhibits some steps of the signaling cascade activated by R, the balance ultimately regulates the platelet capability to aggregate in response to its agonists. Hence, platelet rupture or vessel wall inflammation enhances platelet aggregability via the release of PGE2.
Mentions: PGE2 appears in our study as a molecule playing a role in vascular wall homeostasis through its action in limited healing thrombosis. Indeed, the fact that PGE2 facilitated thrombosis in the arterial flow in response to inflammation indicates that its in vivo effect is sufficient to oppose PGI2. Therefore, even when a small vascular lesion releases or exposes low amounts of agonists, the concentrations of which are below the platelet activation threshold, the presence of PGE2 produced by local inflammation may sensitize platelets and foster healing thrombosis. Conversely, PGI2 produced upon inflammation by neighboring functional endothelial cells limits the extent of thrombosis (32) to restrict it to the lesion. Hence, PGE2 catalyzes healing thrombosis on small lesions, whereas PGI2 restricts its amplification to keep it focalized (Fig. 7).

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