Prostaglandin E ₂ Induces Vascular Relaxation by E-Prostanoid 4 Receptor-Mediated Activation of Endothelial Nitric Oxide Synthase

Abstract

Abstract-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 PGE 2 caused concentration-dependent relaxations during contractions to phenylephrine (EC 50 ϭ5*10 Ϫ8 mol/L). Relaxation after PGE 2 was absent in rings without endothelium and in rings from eNOS Ϫ/Ϫ 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 Ϫ8 mol/L) and mimicked by an EP4 agonist 10 Ϫ7 mol/L) in the presence of endothelium and eNOS only. Relaxations were attenuated significantly in rings from EP4 Ϫ/Ϫ mice but normal in EP2 Ϫ/Ϫ . Inhibitors of the cAMP-protein kinase A pathway attenuated, whereas the inhibitor of protein phosphatase 1C, calyculin (10 Ϫ8 mol/L), abolished the PGE 2 -mediated relaxation. In aortic rings, PGE 2 dephosphorylated eNOS at Thr 495 . Chronically catheterized eNOS Ϫ/Ϫ mice were hypertensive (137Ϯ3.6 mm Hg, nϭ13, versus 101Ϯ3.9 mm Hg, nϭ9) 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. Key Words: cyclooxygenase Ⅲ cGMP Ⅲ hypertension Ⅲ phosphorylation Ⅲ thromboxane P rostaglandin (PG) E 2 is a physiologically important vasodilator in several vascular beds. 1 PGE 2 can bind to and stimulate a family of specific E-prostanoid (EP) receptors with Ն4 distinct subtypes, EP1 to EP4. Of those, the EP2 and EP4 receptors are functionally associated with vasodilatation. 1 EP2 receptors are less abundant than EP4 in most tissues but are involved in the systemic vasodepressor response to PGE 2 infusion, and targeted deletion of EP2 results in salt-sensitive hypertension. 2,3 PGE 2 signaling through the EP4 receptor contributes to the systemic vasodepressor response to PGE 2 in mice, 4,5 attenuates ischemia-reperfusion injury in the heart, 6 and maintains the patency of the ductus arteriosus in fetal life. 7 Experiments with inhibitors of NO synthase have provided data to suggest that NO is an extracellullar mediator for PGE 2 -mediated vasodilatation in various vascular beds. 8,9 Local infusion of cyclooxygenase inhibitors or NO synthase inhibitors in the renal medulla precipitates hypertension, which would be compatible with a serial coupling between the pathways also at this site. 10,...

Microsomal Prostaglandin Synthase-1–Derived Prostaglandin E 2 Protects Against Angiotensin II–Induced Hypertension via Inhibition of Oxidative Stress

“…Increasing evidence indicates that the vascular and renal actions of PGE 2 may be mediated by NO, 15,27 raising a possibility that the NO-cGMP pathway may be affected in mPGES-1 Ϫ/Ϫ mice. We found that Ang II-induced hypertension in mPGES-1 Ϫ/Ϫ mice was associated with a significant reduction of urinary NO x excretion that was restored by Tempol treatment.…”

“…In most vascular beds, PGE 2 serves as a physiologically important vasodilator. 27,28 However, PGE 2 is a potent vasoconstrictor in the tail artery 29 and mesenteric arteries. 30 The vascular effects of PGE 2 is also species dependent.…”

“…41,42 Recently, activation of EP 4 receptors was reported to mediate endotheliumdependent stimulation of endothelial NO synthase activity via dephosphorylation at Thr495. 27 It is possible that the cAMP elevating EP receptors, eg, EP 2 and EP 4 , may coordinately stimulate NO release and inhibit ROS production in the vasculature, thereby shifting the NO-ROS balance to favor vasodilatation. Future studies are needed to determine whether EP 2 or EP 4 is coupled to redox signaling in the vasculature.…”

Roles of Prostaglandin E2 in Cardiovascular Diseases

“…35) The PGE 2 -induced relaxations were mimicked by an ONO-AE1-329 in aortic rings. 36) Recently, we developed a novel EP4 selective agonist (EP4RAG) ( Figure 1H). The EP4RAG was selectively bound to the murine EP4 receptor.…”

2-Ethylpyrazine Induces Vasodilatation by Releasing Nitric Oxide in the Endothelium

“…3) Furthermore, blood flow is regulated by various factors such as nitric oxide (NO) 4) and prostanoids, 5) and the autonomic nerve system. 6) NO plays important roles including causing vasodilatation in the endothelium and controlling physiological conditions.…”