Prostaglandin E2 induces vascular relaxation by E-prostanoid 4 receptor-mediated activation of endothelial nitric oxide synthase
Prostaglandin E2 induces vascular relaxation by E-prostanoid 4 receptor-mediated activation of endothelial nitric oxide synthase
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DOI：
10.1161/hypertensionaha.107.088948
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发表时间：
2007-09-01
期刊：
影响因子：
8.3
通讯作者：
Jensen, Boye L.
中科院分区：
文献类型：
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作者：
Hristovska, Ana-Marija;Rasmussen, Lasse E.;Jensen, Boye L.
本实验旨在检验前列腺素 (PG) E-2 通过激活内皮一氧化氮合酶 ( eNOS) 引起血管舒张的假设。靶向删除 eNOS 和 E-前列腺素 (EP) 受体的小鼠主动脉环用于收缩研究。在清醒的小鼠中测量了 PGE(2) 引起的血压变化。单剂量PGE2在去氧肾上腺素收缩过程中引起浓度依赖性松弛(EC50=5* 10(-8) mol/L)。无内皮环和 eNOS(-/-) 小鼠环中不存在 PGE(2) 后的松弛，并被 N-G-硝基-L-精氨酸甲酯和可溶性鸟苷酸环化酶抑制剂 1H(1,2,4)-恶二唑并-[4,3-a]喹喔啉-1-酮消除。在PGE(2)松弛的主动脉环中，cGMP含量显着增加。仅在内皮和 eNOS 存在的情况下，PGE(2) 诱导的舒张被 EP4 受体拮抗剂 AE3-208 (10(-8) mol/L) 消除，并被 EP4 激动剂 (AE1-329, 10(-7) mol/L) 模拟。 EP4(-/-) 小鼠环中的松弛显着减弱，但 EP2(-/-) 小鼠中则正常。 cAMP-蛋白激酶A途径的抑制剂减弱了，而蛋白磷酸酶1C的抑制剂calyculin (10(-8) mol/L)则消除了PGE2介导的松弛。在主动脉环中，PGE2 在 Thr(495) 处使 eNOS 去磷酸化。长期插管的 eNOS(-/-) 小鼠患有高血压（137 +/- 3.6 mm Hg，n=13，对比 101 +/- 3.9 mm Hg，n=9），与野生型小鼠相比，PGE(2) 降低血压的敏感性较低。对硝苯地平的血压反应没有差异。这些发现表明，PGE(2) 通过 Thr(495) 去磷酸化，引发 EP4 受体介导的内皮依赖性 eNOS 活性刺激，导致鸟苷酸环化酶依赖性血管舒张和主动脉环中 cGMP 的积累。
The present experiments were designed to test the hypothesis that prostaglandin (PG) E-2 causes vasodilatation through activation of endothelial NO synthase ( eNOS). Aortic rings from mice with targeted deletion of eNOS and E-prostanoid (EP) receptors were used for contraction studies. Blood pressure changes in response to PGE(2) were measured in conscious mice. Single doses of PGE2 caused concentration-dependent relaxations during contractions to phenylephrine (EC50=5* 10(-8) mol/L). Relaxation after PGE(2) was absent in rings without endothelium and in rings from eNOS(-/-) mice and was abolished by N-G-nitro-L-arginine methyl ester and the soluble guanylate cyclase inhibitor 1H(1,2,4)-oxadiazolo-[4,3-a] quinoxalin-1-one. In PGE(2)-relaxed aortic rings, the cGMP content increased significantly. PGE(2)-induced relaxations were abolished by the EP4 receptor antagonist AE3-208 (10(-8) mol/L) and mimicked by an EP4 agonist (AE1-329, 10(-7) mol/L) in the presence of endothelium and eNOS only. Relaxations were attenuated significantly in rings from EP4(-/-) mice but normal in EP2(-/-). Inhibitors of the cAMP-protein kinase A pathway attenuated, whereas the inhibitor of protein phosphatase 1C, calyculin (10(-8) mol/L), abolished the PGE2-mediated relaxation. In aortic rings, PGE2 dephosphorylated eNOS at Thr(495). Chronically catheterized eNOS(-/-) mice were hypertensive (137 +/- 3.6 mm Hg, n=13, versus 101 +/- 3.9 mm Hg, n=9) and exhibited a lower sensitivity of blood pressure reduction in response to PGE(2) compared with wild-type mice. There was no difference in the blood pressure response to nifedipine. These findings show that PGE(2) elicits EP4 receptor-mediated, endothelium-dependent stimulation of eNOS activity by dephosphorylation at Thr(495) resulting in guanylyl cyclase-dependent vasorelaxation and accumulation of cGMP in aortic rings.