Published Online
on July 16, 2007

A more recent version of this article appeared on September 1, 2007

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Submitted on February 14, 2007
Revised on March 12, 2007

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; and 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.

^* To whom correspondence should be addressed. E-mail: bljensen{at}health.sdu.dk.

Abstract--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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