Myometrial Activation and Preterm Labour: Evidence Supporting a Role for the Prostaglandin F Receptor—A Review

Olson, David M.; Zaragoza, Dean B.; Shallow, M.; Cook, Jocelyn L; Mitchell, Bryan F.; Grigsby, Peta L.; Hirst, Jonathan J.

doi:10.1053/plac.2002.0938

Cited by 54 publications

(35 citation statements)

References 56 publications

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“…S2). Results showed that PDC113.824 significantly reduced both the strength and duration of both PGF2␣-induced and spontaneous myometrial contraction in a dose-dependent manner, consistent with the increased expression of FP in the uterus during labor, which occurs even in rodents (6). Taken together, our results suggest that PDC113.824 delays both term and preterm labor, at least in part through the inhibition of uterine contraction.…”

Section: Design and Optimization Of The Peptidomimetic Pdc113824-supporting

confidence: 79%

“…They are initiators of physiological labor and exert their effects through different G protein-coupled receptors (GPCRs). 6 For instance, prostaglandin F2␣ (PGF2␣) promotes myometrial contraction through activation of PGF2␣ (FP) receptors (5,6). Moreover, FP receptor null mice fail to deliver at term and are unresponsive to induced labor mediated by either PGF2␣ or the uterogenic hormone oxytocin (7,8).…”

mentioning

confidence: 99%

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A Novel Biased Allosteric Compound Inhibitor of Parturition Selectively Impedes the Prostaglandin F2α-mediated Rho/ROCK Signaling Pathway

Goupil

Tassy

Bourguet

et al. 2010

Journal of Biological Chemistry

113

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The prostaglandin F2␣ (PGF2␣) receptor (FP) is a key regulator of parturition and a target for pharmacological management of preterm labor. However, an incomplete understanding of signaling pathways regulating myometrial contraction hinders the development of improved therapeutics. Here we used a peptidomimetic inhibitor of parturition in mice, PDC113.824, whose structure was based on the NH 2 -terminal region of the second extracellular loop of FP receptor, to gain mechanistic insight underlying FP receptor-mediated cell responses in the context of parturition. We show that PDC113.824 not only delayed normal parturition in mice but also that it inhibited both PGF2␣-and lipopolysaccharide-induced preterm labor. PDC113.824 inhibited PGF2␣-mediated, G␣ 12 -dependent activation of the Rho/ROCK signaling pathways, actin remodeling, and contraction of human myometrial cells likely by acting as a non-competitive, allosteric modulator of PGF2␣ binding. In contrast to its negative allosteric modulating effects on Rho/ROCK signaling, PDC113.824 acted as a positive allosteric modulator on PGF2␣-mediated protein kinase C and ERK1/2 signaling. This bias in receptor-dependent signaling was explained by an increase in FP receptor coupling to G␣ q , at the expense of coupling to G␣ 12 . Our findings regarding the allosteric and biased nature of PDC113.824 offer new mechanistic insights into FP receptor signaling relevant to parturition and suggest novel therapeutic opportunities for the development of new tocolytic drugs.

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Section: Design and Optimization Of The Peptidomimetic Pdc113824-supporting

confidence: 79%

mentioning

confidence: 99%

A Novel Biased Allosteric Compound Inhibitor of Parturition Selectively Impedes the Prostaglandin F2α-mediated Rho/ROCK Signaling Pathway

Goupil

Tassy

Bourguet

et al. 2010

Journal of Biological Chemistry

113

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“…The temporal profile of uterine electrical activity was similar to that of UOV PGF 2 , lagging behind it by approximately 12 h, consistent with a pivotal role for PGF 2 in the regulation of uterotonic activity (Olson et al 1985) and our recent finding that the selective inhibition of PGF 2 action markedly suppresses uterine activity (Olson 2003).…”

Section: Discussionsupporting

confidence: 86%

Changes in the expression of prostaglandin E and F synthases at induced and spontaneous labour onset in the sheep

Palliser¹,

Gt²,

Hirst³

et al. 2004

Journal of Endocrinology

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The differential production of prostaglandin (PG) F 2 and PGE 2 within the uterine compartment may play a role in controlling myometrial contraction. We hypothesized that the enzymes downstream of PG endoperoxide synthase-2 (PGHS-2) determine the ratio of PGF 2 and PGE 2 in the utero-ovarian vein plasma and the time of normal and preterm labour onset. The aim of this study was to simultaneously determine the expression of PGF and PGE synthases (PGFS and PGES) in gestational tissues at spontaneous and induced-preterm labour in sheep. Myometrial, endometrial and placental tissue were obtained from ewes in dexamethasone-induced preterm labour, age-matched control ewes, and ewes in spontaneous term labour for analysis of mRNA expression by real-time PCR. PGFS mRNA expression was significantly increased following dexamethasone-induced and spontaneous labour onset in placentome (P,0·01) but was unchanged in the myometrium and endometrium. In contrast, PGES mRNA expression remained unchanged or decreased. PGHS-2 mRNA expression was increased in all tissues examined in both dexamethasone-induced and spontaneous labour (P,0·001). Plasma PGE 2 and PGF 2 concentrations rose in both dexamethasoneinduced and spontaneous labour with the ratio of PGF 2 :PGE 2 increased with labour onset (P,0·05). These results are consistent with the hypothesis that the increased expression, of PGFS is responsible for the increased PGF 2 :PGE 2 ratio and this, together with increased PGHS-2 expression, accounts for myometrial activity at labour onset. The findings point to PGFS expression as a key factor in regulating the uterotonic process in the sheep.

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“…Prostaglandins are critical molecules for initiation of parturition (reviewed in Ref. 32) and are currently used to trigger delivery in humans. PCDH12 levels may thus influence the timing of birth through regulation of prostaglandin activity.…”

Section: Discussionmentioning

confidence: 99%

Protocadherin 12 deficiency alters morphogenesis and transcriptional profile of the placenta

Rampon

Bouillot

Climescu-Haulica

et al. 2008

Physiological Genomics

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Protocadherins are transmembrane proteins exhibiting homophilic adhesive activities through their extracellular domain. Protocadherin 12 ( Pcdh12) is expressed in angiogenic endothelial cells, mesangial cells of kidney glomeruli, and glycogen cells of the mouse placenta. To get insight into the role of this protein in vivo, we analyzed PCDH12-deficient mice and investigated their placental phenotype. The mice were alive and fertile; however, placental and embryonic sizes were reduced compared with wild-type mice. We observed defects in placental layer segregation and a decreased vascularization of the labyrinth associated with a reduction in cell density in this layer. To understand the molecular events responsible for the phenotypic alterations observed in Pcdh12−/− placentas, we analyzed the expression profile of embryonic day 12.5 mutant placentas compared with wild-type placentas, using pangenomic chips: 2,289 genes exhibited statistically significant changes in expressed levels due to loss of PCDH12. Functional grouping of modified genes was obtained by GoMiner software. Gene clusters that contained most of the differentially expressed genes were those involved in tissue morphogenesis and development, angiogenesis, cell-matrix adhesion and migration, immune response, and chromatin remodeling. Our data show that loss of PCDH12 leads to morphological alterations of the placenta and to notable changes in its gene expression profile. Specific genes emerging from the microarray screen support the biological modifications observed in PCDH12-deficient placentas.

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Myometrial Activation and Preterm Labour: Evidence Supporting a Role for the Prostaglandin F Receptor—A Review

Cited by 54 publications

References 56 publications

A Novel Biased Allosteric Compound Inhibitor of Parturition Selectively Impedes the Prostaglandin F2α-mediated Rho/ROCK Signaling Pathway

A Novel Biased Allosteric Compound Inhibitor of Parturition Selectively Impedes the Prostaglandin F2α-mediated Rho/ROCK Signaling Pathway

Changes in the expression of prostaglandin E and F synthases at induced and spontaneous labour onset in the sheep

Protocadherin 12 deficiency alters morphogenesis and transcriptional profile of the placenta

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