Reproductive failure and reduced blood pressure in mice lacking the EP2 prostaglandin E2 receptor

Tilley, Stephen L.; Audoly, Laurent; Hicks, Elizabeth; Kim, Hyung Suk; Flannery, Patrick J.; Coffman, Thomas M.; Koller, Beverly H.

doi:10.1172/jci6579

Cited by 233 publications

(138 citation statements)

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“…To our knowledge this is the first published report to demonstrate the importance of mPGES1 in inflammatory pain and in a model of chronic inflammation. The complexity of the enzymatic and nonenzymatic pathways that are responsible for the conversion of the metabolite of cyclooxygenases into specific PGs has until now made it difficult to identify other possible targets for intervention in prostaglandin-mediated inflammation (43,44). Taking these findings together, we suggest that mPGES1 represents a target for the treatment of inflammatory disease such as arthritis that will spare important physiological systems in which other PGs participate.…”

Section: Resultsmentioning

confidence: 94%

Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase

Trebino

Stock

Gibbons

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Prostaglandin (PG)E2 is a potent mediator of pain and inflammation, and high levels of this lipid mediator are observed in numerous disease states. The inhibition of PGE2 production to control pain and to treat diseases such as rheumatoid arthritis to date has depended on nonsteroidal antiinflammatory agents such as aspirin. However, these agents inhibit the synthesis of all prostanoids. To produce biologically active PGE2, PGE synthases catalyze the isomerization of PGH2 into PGE2. Recently, several PGE synthases have been identified and cloned, but their role in inflammation is not clear. To study the physiological role of the individual PGE synthases, we have generated by targeted homologous recombination a mouse line deficient in microsomal PGE synthase 1 (mPGES1) on the inbred DBA͞1lacJ background. mPGES1-deficient (mPGES1 ؊/؊ ) mice are viable and fertile and develop normally compared with wild-type controls. However, mPGES1 ؊/؊ mice displayed a marked reduction in inflammatory responses compared with mPGES1 ؉/؉ mice in multiple assays. Here, we identify mPGES1 as the PGE synthase that contributes to the pathogenesis of collagen-induced arthritis, a disease model of human rheumatoid arthritis. We also show that mPGES1 is responsible for the production of PGE 2 that mediates acute pain during an inflammatory response. These findings suggest that mPGES1 provides a target for the treatment of inflammatory diseases and pain associated with inflammatory states.arthritis ͉ inflammation ͉ macrophage ͉ knockout ͉ PGE2

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Section: Resultsmentioning

confidence: 94%

Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase

Trebino

Stock

Gibbons

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…The PGE receptor subtype PTGER2, however, is more important for fertility. Mice lacking the gene encoding PTGER2 suffer from decreased ovulation and fertilization (Tilley et al, 1999). The present study shows that blocking PTGER2 receptors using the selective antagonist AH6809 significantly reduced oocyte maturation rate (about 20% reduction).…”

Section: Discussionmentioning

confidence: 99%

Role of PTGS2-generated PGE2 during gonadotrophin-induced bovine oocyte maturation and cumulus cell expansion

Marei

Abayasekara

Wathes

et al. 2014

Reproductive BioMedicine Online

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(AA Fouladi-Nashta).Waleed Fawzy A Marei is a veterinarian and graduated from Cairo University, Egypt in 2001. He started his academic career in theriogenology in 2002 and obtained his MSc degree in 2005. He joined the reproduction research group at the Royal Veterinary College, London, UK and investigated the effects of fatty acids on oocyte quality and early embryo development for his PhD, awarded in 2010. He then pursued post-doctoral research in the same group, working on early embryo development and implantation. Currently, he is a lecturer on theriogenology at Cairo University. His interests are clinical applications of assisted reproduction technologies and feed additives to improve reproductive performance in farm animals.Abstract Prostaglandin E 2 (PGE 2 ) is an autocrine/paracrine factor which mediates gonadotrophin (Gn) stimulation of cumulus expansion and oocyte maturation in rodents. Its role in bovine oocyte maturation is less characterized. This study detected PTGS2 (COX2) and PGE synthases (PTGES1, PTGES2 and PTGES3) in bovine cumulus-oocyte complexes (COC). Only PTGS2 and PTGES1 expression changed during maturation. In Gn-free media, no cumulus expansion and $45% nuclear maturation was achieved, while Gn-induced maturation showed full cumulus expansion (score 3) and $87% maturation. PGE 2 supplementation without Gn induced mild cumulus expansion (score 0.5-1) but increased nuclear maturation to levels similar to those obtained with Gn alone. In the presence of Gn, exogenous PGE 2 did not affect expansion or nuclear maturation and subsequent embryo development. Treatment with PTGS2 selective inhibitor (NS398), PTGS2-specific siRNA or PTGER2-receptor antagonist (AH6809) resulted in $20-25% reduction in nuclear maturation. NS398 and AH6809 did not affect cumulus expansion. Most oocytes not reaching metaphase of second meiosis (MII) following NS398, AH6809 and PTGS2-specific siRNA treatments were at MI. After longer maturation, NS398-treated oocytes had normal MII rate and uncompromised embryo development. PGE 2 has a limited role in cumulus expansion in bovine COC but is important for the timing of Gn-induced nuclear maturation. RBMOnline

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“…40 Mice lacking EP 2 develop salt-sensitive hypertension. 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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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Abstract-Prostaglandin (PG) E 2 has an established role in the regulation of vascular tone and reactivity. The present study examined the role and mechanism of microsomal PG synthase-1 (mPGES-1) in vascular response to angiotensin II (Ang II) infusion. A 7-day Ang II infusion at 0.35 mg/kg per day via osmotic minipump had no obvious effect on mean arterial blood pressure in mPGES-1 ϩ/ϩ mice but induced a marked hypertensive response in mPGES-1 Ϫ/Ϫ mice, associated with a parallel increase in urinary 8-isoprostane excretion and aortic NADPH oxidase activity and mRNA expression of p47 phox , gp91 phox , and Nox1. The hypertension in mPGES-1 Ϫ/Ϫ mice was completely prevented by Tempol treatment and was fully restored on termination of the antioxidant. Apocynin induced a similar blood pressure-lowering effect as Tempol. The Ang II infusion induced mRNA expression of mPGES-1, as well as mPGES-2 and cytosolic PGE synthase in the aortas as assessed by real-time RT-PCR. Immunohistochemistry revealed remarkably enhanced immunoreactivity of mPGES-1 mostly in vascular smooth muscle cells. In cultured vascular smooth muscle cells, Ang II exerted a direct stimulatory effect on reactive oxygen species production, NADPH oxidase activity, and expression of p47 phox , gp91 phox , and Nox1 that were all inhibited by PGE 2 . The Ϫ/Ϫ mice also exhibited enhanced renal hemodynamic response to acute Ang II infusion at 150 nmol/kg per minute via a jugular vein over a period of 40 minutes. These results suggest that mPGES-1-derived PGE 2 buffers Ang II-induced vasoconstriction via inhibition of NADPH oxidase-dependent reactive oxygen species production. Key Words: mPGES-1 Ⅲ angiotensin II Ⅲ mean arterial pressure Ⅲ oxidative stress Ⅲ NADPH oxidase P rostaglandin (PG) E 2 is a major product of arachidonic acid metabolism, being implicated in pain and inflammatory responses, as well as in the regulation of various physiological functions. 1 The biosynthesis of PGE 2 requires 3 sequential steps of the cyclooxygenase pathway: the release of arachidonic acid from membrane glycerophospholipids by phospholipase A 2 , conversion of arachidonic acid to the unstable intermediate PGH 2 by cyclooxygenase-1 or cyclooxygenase-2, and isomerization of PGH 2 to PGE 2 by PGE synthase (PGES). 2,3 To date, Ն3 major forms of PGES have been cloned and characterized: membrane-associated PGES (mPGES)-1, mPGES-2, and cytosolic PGES (cPGES). 3 Several recent studies using mPGES-1-deficient mice demonstrate a major role of mPGES-1 in pain and inflammatory responses. 4,5 The cardiovascular consequences associated with cyclooxygenase-2 inhibitors 6 -9 have stimulated the interest regarding mPGES-1 as a potential target for the next generation of anti-inflammatory drugs. 10

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Reproductive failure and reduced blood pressure in mice lacking the EP2 prostaglandin E2 receptor

Cited by 233 publications

References 34 publications

Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase

Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase

Role of PTGS2-generated PGE2 during gonadotrophin-induced bovine oocyte maturation and cumulus cell expansion

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

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Reproductive failure and reduced blood pressure in mice lacking the EP2 prostaglandin E2 receptor

Cited by 233 publications

References 34 publications

Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase

Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase

Role of PTGS2-generated PGE2 during gonadotrophin-induced bovine oocyte maturation and cumulus cell expansion

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

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