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(Hypertension. 2007;50:525.)
© 2007 American Heart Association, Inc.

Original Articles

Prostaglandin E₂ Induces Vascular Relaxation by E-Prostanoid 4 Receptor-Mediated Activation of Endothelial Nitric Oxide Synthase

Ana-Marija Hristovska; Lasse E. Rasmussen; Pernille B.L. Hansen; Susan S. Nielsen; Rolf M. Nüsing; Shuh Narumiya; Paul Vanhoutte; Ole Skøtt; Boye L. Jensen

From the Department of Physiology and Pharmacology (A-M.H., L.E.R., P.B.L.H., S.S.N., O.S., B.L.J.), University of Southern Denmark, Odense, Denmark; Institute of Clinical Pharmacology (R.M.N.), Johann Wolfgang Goethe-University, Frankfurt, Germany; Department of Pharmacology (P.V.), University of Hong Kong, Hong Kong; and the Department of Pharmacology (S.N.), Kyoto University Faculty of Medicine, Kyoto, Japan.

Correspondence to Boye L. Jensen, Department of Physiology and Pharmacology, University of Southern Denmark, Winslowparken 21, 3, DK-5000 Odense C, Denmark. E-mail: bljensen{at}health.sdu.dk

The present experiments were designed to test the hypothesis that prostaglandin (PG) E₂ 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 PGE₂ 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 PGE₂ 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 PGE₂-relaxed aortic rings, the cGMP content increased significantly. PGE₂-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 Thr⁴⁹⁵. 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 PGE₂ compared with wild-type mice. There was no difference in the blood pressure response to nifedipine. These findings show that PGE₂ elicits EP4 receptor-mediated, endothelium-dependent stimulation of eNOS activity by dephosphorylation at Thr⁴⁹⁵ resulting in guanylyl cyclase–dependent vasorelaxation and accumulation of cGMP in aortic rings.

Key Words: cyclooxygenase • cGMP • hypertension • phosphorylation • thromboxane

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