Limits...
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.

Show MeSH

Related in: MedlinePlus

In vivo Rose bengal–induced oxidative stress of endothelium does not stimulate local production of PGE2. (A) Representative images of thrombosis (green light) induced by oxidative stress due to laser excitation of Rose bengal. Only a few clots are formed at 4 s, whereas massive thrombosis is already seen at 45s. Arrows indicate carotid walls. (B) Amount of PGE2 detected in carotid tissue after 4 or 45 s of oxidative stress, showing that PGE2 was not increased at the beginning of thrombosis (compare with Fig. 1 A), nor when thrombosis was massive. Horizontal lines indicate the mean value for each group.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2118736&req=5

fig3: In vivo Rose bengal–induced oxidative stress of endothelium does not stimulate local production of PGE2. (A) Representative images of thrombosis (green light) induced by oxidative stress due to laser excitation of Rose bengal. Only a few clots are formed at 4 s, whereas massive thrombosis is already seen at 45s. Arrows indicate carotid walls. (B) Amount of PGE2 detected in carotid tissue after 4 or 45 s of oxidative stress, showing that PGE2 was not increased at the beginning of thrombosis (compare with Fig. 1 A), nor when thrombosis was massive. Horizontal lines indicate the mean value for each group.

Mentions: To further ascertain that platelet production of PGE2 does not alter aggregation in vivo, we looked for a model of thrombosis in which mural PGE2 is not produced when thrombosis starts. We tested a model of endothelial injury induced by oxidative stress resulting from local excitation of Rose bengal by a laser beam. Under standard conditions (21), we observed that a few clots were already visible at 4 s and that 80% of the arterial diameter was visually obstructed at 45 s (Fig. 3 A). PGE2 levels in these injured carotids were found in the range of control values and were not significantly different between 4 s (55 ± 6 pg/carotid; n = 6) and 45 s (73 ± 11 pg/carotid; n = 6; P > 0.05; Fig. 3 B). Thus, we used this model deprived of PGE2 at the initiation of thrombosis to examine whether aggregating platelets could produce enough PGE2 to alter amplification of thrombosis. Consistent with our in vitro data, carotids of Ep3−/− mice infused with EP3-deficient platelets were totally occluded after 30 min of laser exposure, as were WT mice (n = 5 in each group). We concluded that platelets did not produce enough PGE2 in vivo to facilitate amplification. Collectively, our data show that thrombosis is facilitated primarily by arterial wall–produced 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)

In vivo Rose bengal–induced oxidative stress of endothelium does not stimulate local production of PGE2. (A) Representative images of thrombosis (green light) induced by oxidative stress due to laser excitation of Rose bengal. Only a few clots are formed at 4 s, whereas massive thrombosis is already seen at 45s. Arrows indicate carotid walls. (B) Amount of PGE2 detected in carotid tissue after 4 or 45 s of oxidative stress, showing that PGE2 was not increased at the beginning of thrombosis (compare with Fig. 1 A), nor when thrombosis was massive. Horizontal lines indicate the mean value for each group.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: In vivo Rose bengal–induced oxidative stress of endothelium does not stimulate local production of PGE2. (A) Representative images of thrombosis (green light) induced by oxidative stress due to laser excitation of Rose bengal. Only a few clots are formed at 4 s, whereas massive thrombosis is already seen at 45s. Arrows indicate carotid walls. (B) Amount of PGE2 detected in carotid tissue after 4 or 45 s of oxidative stress, showing that PGE2 was not increased at the beginning of thrombosis (compare with Fig. 1 A), nor when thrombosis was massive. Horizontal lines indicate the mean value for each group.
Mentions: To further ascertain that platelet production of PGE2 does not alter aggregation in vivo, we looked for a model of thrombosis in which mural PGE2 is not produced when thrombosis starts. We tested a model of endothelial injury induced by oxidative stress resulting from local excitation of Rose bengal by a laser beam. Under standard conditions (21), we observed that a few clots were already visible at 4 s and that 80% of the arterial diameter was visually obstructed at 45 s (Fig. 3 A). PGE2 levels in these injured carotids were found in the range of control values and were not significantly different between 4 s (55 ± 6 pg/carotid; n = 6) and 45 s (73 ± 11 pg/carotid; n = 6; P > 0.05; Fig. 3 B). Thus, we used this model deprived of PGE2 at the initiation of thrombosis to examine whether aggregating platelets could produce enough PGE2 to alter amplification of thrombosis. Consistent with our in vitro data, carotids of Ep3−/− mice infused with EP3-deficient platelets were totally occluded after 30 min of laser exposure, as were WT mice (n = 5 in each group). We concluded that platelets did not produce enough PGE2 in vivo to facilitate amplification. Collectively, our data show that thrombosis is facilitated primarily by arterial wall–produced 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