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Department of Physiology,3 Monash University, Victoria 3800, Australia
Prince Henry's Institute of Medical Research,4 Clayton, Victoria 3168, Australia
Department of Obstetrics and Gynecology,5 University of Melbourne, Mercy Hospital for Women, East Melbourne, Victoria 3002, Australia
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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acting on prostaglandin E (EP) and prostaglandin F (FP) receptors, respectively. Activation of FP receptors strongly stimulates the myometrium, whereas stimulation of EP receptors may lead to contraction or relaxation, depending on the EP subtype (EP1–4) expression. Thus, the relative expression of FP and EP1–4 may determine the responsiveness to PGE2 and PGF2. The aims of this study were to characterize the expression of EP1–4 and FP in intrauterine tissues and placentome, together with myometrial responsiveness to PG, following the onset of dexamethasone-induced preterm and spontaneous term labor. Receptor mRNA expression was measured using quantitative real-time polymerase chain reaction using species-specific primers. There was no increase in myometrial contractile receptor expression at labor onset, nor was there a change in sensitivity to PGE2 and PGF2. This suggests expression of these receptors reaches maximal levels by late gestation in sheep. Placental tissue showed a marked increase in EP2 and EP3 receptor expression, the functions of which are unknown at this time. Consistent with previous reports, these results suggest that PG synthesis is the main factor in the regulation of uterine contractility at labor. This is the first study to simultaneously report PG E and F receptor expression in the key gestational tissues of the sheep using species-specific primers at induced-preterm and spontaneous labor onset.
parturition, placenta, pregnancy, uterus
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, play a pivotal role in the initiation and progression of normal and preterm labor. Rising production of these PGs by intrauterine tissues has been widely implicated as the key mechanism underlying increased uterine activity at labor. Attention has also focused recently on the potential role of tissue responsiveness to PGs in late gestation, especially on the possibility that changing patterns of PG receptor expression may contribute to the induction of preterm labor.
Prostaglandins are released immediately after synthesis, and their short half-lives and pulmonary inactivation imply that they act most efficaciously close to their site of production. The actions of PGs are mediated by specific receptors on plasma membranes of target cells that lead to the stimulation of distinct second-messenger pathways [1]. Prostaglandin receptors are classified into five subtypes (DP, EP, FP, IP, and TP) on the basis of their sensitivity to the five primary prostanoids (PGD2, PGE2, PGF2, PGI2, and TXA2), respectively [1]. There are four known subtypes of the PGE2 receptor (EP1, EP2, EP3, and EP4), each encoded by a separate gene. The existence of EP subtypes potentially explains the widely heterogeneous biological responses that are exerted by PGE2 between different tissues. PG receptors are coupled via G proteins to the second messengers cAMP, inositol triphosphate, or intracellular calcium release. EP2 and EP4 stimulate adenylate cyclase and cAMP production via the G protein Gs leading to smooth muscle relaxation. FP and EP1 increase phosphoinositol turnover and calcium mobilization, with the resultant increase in intracellular free Ca2+, leading to smooth muscle contraction. EP3 receptors may also be coupled with the G protein Gi, inhibiting adenylate cyclase and lowering cAMP, thereby facilitating uterine contractions [1, 2].
Recent studies in human tissue and in nonhuman primates and sheep have reported that stimulatory PG receptor expression increases, or relaxatory PG receptor expression decreases, in the myometrium at term labor [3–5]. These studies suggest that up-regulation of stimulatory PG receptors potentiates the uterotonic activity of PGs or, alternatively, that the ratio of expression of the stimulatory versus relaxatory receptors may determine tissue contractility in response to PGs at parturition. Ma et al. [3] have reported an increase in EP3, EP4, and FP, but no change in EP2 mRNA expression in ovine myometrium at the time of spontaneous labor. However, these studies used human-derived primers. Previous in vitro studies using sheep myometrial strips have reported an increase in responsiveness to exogenous PGE2 and PGF2 during gestation. Responsiveness reached maximal levels by gestational age (GA) 126–135 with no further increase with labor onset [6], suggesting no further change in the pattern of FP or EP receptor expression.
In the sheep, circulating PGE2 concentrations rise steadily during the second half of gestation and PGF2 concentrations increase immediately before the onset of labor [7– 11]. Whittle et al. [12, 13] have suggested the increase in PGE2 and consequent EP receptor activation may contribute to the stimulation of estradiol output by the placenta, thereby augmenting the uterotonic cascade. However, reports on the expression of EP receptors in the sheep placenta are lacking.
We hypothesized that excitatory PG receptor expression increases, or inhibitory PG receptor expression decreases, or both, in the myometrium at preterm labor onset, and that the consequent rise in sensitivity to the uterotonic PGs contributes to the onset and progression of preterm labor. We further reasoned that information about the expression of PG receptors in the placenta may offer further insight into the labor mechanism by elucidating the potential role of receptor changes in the regulation of placental estradiol and PG synthesis. To address these hypotheses we measured the expression of mRNA for FP and EP1–4 in ovine myometrium, endometrium, and placentomes in dexamethasone-induced preterm labor and spontaneous term labor. Myometrial responsiveness to PGF2 and PGE2 was determined in the same tissues, allowing comparison of PG receptor expression with tissue responsiveness as a measure of the net biological effect of any changes in receptor expression. In addition, PG receptor expression was correlated with the previously reported expression of specific PG synthases in uterine tissues and the concentrations of PGE2 and PGF2 in uterine venous plasma of the same animals [11]. To our knowledge, this is the first study to simultaneously report PG E and F receptor expression in the key gestational tissues of the sheep using species-specific primers at labor onset.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental procedures were approved by and conducted in accordance with the Physiology Animal Ethics Committee of Monash University. The animals used in this study were also used in a previously published study [11]. Twelve pregnant Border Leicester-Merino crossbred ewes of known gestational age (GA, days) underwent surgery to implant fetal and maternal carotid artery and jugular vein catheters at GA 124– 127. Utero-ovarian vein (UOV) catheters were placed in both horns of the uterus (UOV hormone concentrations are from the horn ipsilateral to the catheterized fetus) as previously described [11]. A small piece of myometrium (
2.5 x 1 cm) was excised from the uterine wall incision for immediate in vitro contractility study. Electromyogram (EMG) electrodes were sewn into the myometrium to monitor myometrial activity. Uterine EMG activity was recorded continuously on a Grass polygraph (Grass Instruments, West Warwick, RI) using a Grass 7P3 preamplifier with 3 Hz high pass filtering. The recordings were used to determine when parturition was imminent.
Ewes were randomly assigned to one of three groups. In a spontaneous labor group (n = 4), uterine EMG activity was monitored and plasma samples were taken daily until late in the second stage of spontaneous labor (146 ± 1.3 GA). Another group (n = 4) received a continuous fetal i.v. dexamethasone infusion (1 mg/day in sterile saline at 1 ml/h) from 135 days GA [14] to induce preterm labor. A saline-infused control group (n = 4) received a continuous saline infusion from 135 to 138 GA when the ewes were killed for tissue collection (equivalent to the time of imminent delivery in the dexamethasone-treated ewes). Ewes in dexamethasone-induced and spontaneous labor groups were killed in advanced second-stage labor when the fetal head was visible or palpable in the vagina. All ewes were killed by barbiturate overdose and the uteri quickly exteriorized. Samples of myometrium, endometrium, and placentomes from the midsection of the uterus were removed and immediately snap-frozen in liquid nitrogen and stored at –70°C for subsequent RNA extraction. Myometrium was also collected for immediate in vitro contractility study.
Real-Time Polymerase Chain Reaction Measurement of PG Receptor Expression
Methods for quantification of gene expression have previously been described [11]. Briefly, sense and antisense oligonucleotide primers were designed from reported ovine sequences for FP [15] and EP1–4 [16] (Table 1). Netprimer (Premier BioSoft, Palo Alto, CA), Genefisher and Amplify software (University of Wisconsin, Madison, WI) were used to design and optimize primers with stringency conditions of length (20–25 base pairs), melting temperature (55–80°C), GC content (50%), primer dimer formation, and self-priming formation. The Basic Local Alignment Search Tool (BLAST) was used to determine that the primers bound exclusively to the specific RNA of interest and primers were custom-made by Sigma Genosys (Sydney, Australia).
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Qiagen RNeasy kits (Clifton Hill, Victoria, Australia) were used to extract total RNA from 150 mg of snap-frozen myometrial, endometrial, and placentome tissue according to the manufacturer's instructions. Total RNA (2 µg) from myometrium, endometrium, and placenta was reverse-transcribed (Expand RT, Roche Molecular), and the product stored at –20°C until required for use in real-time polymerase chain reaction (PCR). Appropriate cDNAs to be used as standards in real-time PCR quantification were generated by conventional PCR on a thermal block cycler (PCR Express Machine, Thermo Hybaid, Middlesex, U.K.) using corresponding primer pairs that were used in the real-time PCR quantification (Table 1). Purified PCR products were sequenced by the Wellcome Trust Sequencing Center (Prince Henry's Institute of Medical Research and the Monash Institute of Reproduction and Development) using an ABI Prism TM 377 DNA Sequencer (Perkin-Elmer Biosystems, Foster City, CA). Sequenced PCR products were verified against the nucleotide database using the National Center for Biotechnology Information nucleotide-nucleotide BLAST search. All sequences showed 100% homology to the published ovine sequences. Sequence-confirmed purified PCR products were used as standards in real-time PCR quantification. In all cases, the cDNA standards used were identical to the real-time PCR products to ensure equal amplification efficiency between standards and PCR products. Quantification of relative mRNA abundance for FP, EP1, EP2, EP3, and EP4 was performed by real-time PCR amplification in a LightCycler (Roche) instrument using SYBR green I fluorescence detection of amplified products (as described in [11]). The primer pairs, optimal MgCl2 concentrations, and the dilution of reverse transcription products used in the real-time PCR analysis are shown in Table 1. Data obtained from the LightCycler were normalized against 18S ribosomal RNA, which was quantified by electrophoresing equivalent amounts of RNA (0.6 µg) on an agarose gel and the 18S ribosomal RNA fluorescence measured using a CCD camera with Quantity One 5.1 software (Bio-Rad, NSW, Australia). All measurements were performed within the linear range under nonsaturating pixel conditions. The electrophoresed RNA was also used to confirm the integrity of all RNAs used in the real-time PCR analysis.
Myometrial Responsiveness to PGs In Vitro
Myometrium was obtained both during the initial surgery and in labor (see above), and transferred to the laboratory in cold physiological saline solution (PSS; containing 120 mM NaCl, 5 mM KCl, 25 mM NaHCO3, 1 mM MgSO4, 1.2 mM KH2PO4, 11 mM glucose, and 2.5 mM CaCl2; gassed with 5% CO2, 95% O2). Eight ewes of the same gestational age receiving no treatment (control) were also used. Strips of longitudinal smooth muscle were freed of circular myometrium and serosa, and endometrium and large blood vessels were removed from circular smooth muscle (strips approximately 10 mm long and weighing 3–5 mg) and transferred to an organ bath of continuously oxygenated PSS at 35°C. Strips were mounted for isometric tension recording using a Grass FT03C transducer. Each strip was stretched to 1–2 g tension and rested for 1 h. All tissues were tested twice with PSS containing 40 mM K+ (Na+ replacement) (HiK). Following 20 min of rest, PGF2 or PGE2 were added to the bath in increasing concentrations. Each strip was subjected to one protocol only, using either PGE2 or PGF2. Spontaneous contractile activity in one time-control each of longitudinal and circular myometrium from every ewe was constant over the test period. Myometrial contractions (isometric tension development) were recorded and analyzed using PowerLab. Tension was expressed as a percentage of the final response to HiK PSS.
Statistical Analysis
Concentration/tension curves were fitted and analyzed statistically using Prism software (GraphPad Software, Inc, CA), which determined maximum tension TMAX and pD2 (dissociation constant, –log EC50). All data were tested for homogeneity of variance and transformed if necessary to achieve homogeneity. The effects of stage of pregnancy (not in labor, NIL; versus in labor, IL) were analyzed using repeated measures two-way analysis of variance (ANOVA). Multifactorial ANOVA was used to determine the effects of tissue and treatment on mean mRNA expression. Where significant effects were found by ANOVA, differences between individual mean values were detected with subsequent least significance differences tests. Data are presented as the mean ± SEM, and significant differences are reported at the P < 0.05, 0.01, or 0.001 levels.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Myometrium The abundance of FP, EP3, and EP4 mRNA (Fig. 1A) remained unchanged between late gestation and following labor onset. Of interest, FP mRNA expression in tissue from dexamethasone-induced ewes exceeded that in ewes with spontaneous labor (P < 0.01). EP2 mRNA expression was increased in association with spontaneous labor (P < 0.01) compared with that of controls. EP1 mRNA could not be detected in this or any other gestational tissue examined, and no further results are reported for this receptor type.
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Placentome The relative abundance of FP, EP2, EP3, and EP4 mRNA in the placentome is shown in Figure 1B. There was a significant increase in FP mRNA expression in the placentomes of dexamethasone-induced ewes compared with the gestational age matched controls and in ewes following the onset of spontaneous labor (P < 0.001). EP2 mRNA expression was markedly higher following both dexamethasone-induced and spontaneous labor compared with that of controls (P < 0.05). EP3 mRNA expression in the placentome showed a significant increase in both laboring groups compared with controls (P < 0.05). There was also a significant difference between the laboring groups in EP3 mRNA expression, with higher expression following dexamethasone-induced labor (P < 0.05). There was a significant increase in placentome EP4 mRNA expression in the ewes with spontaneous labor compared with that of controls and dexamethasone-induced ewes alike (P < 0.05); however, there was no difference in expression between the dexamethasone-induced group versus controls, and this mRNA was of very low abundance.
Endometrium No change was found in FP mRNA expression in the endometrium after either dexamethasone-induced or spontaneous labor (Fig. 1C). Both laboring tissue groups exhibited increased endometrial EP2 mRNA expression compared with that of controls (P < 0.05). There was a significant decrease in EP3 mRNA expression in spontaneous labor (P < 0.01), and no difference was observed in the dexamethasone-induced group compared with controls. The expression of EP4 was significantly elevated following dexamethasone-induced labor (P < 0.01) compared with controls.
Relative PG Receptor Expression Differences Between Tissues
Differences in PG receptor expression between tissues are shown in Figure 2. There was a significant effect of tissue for all four genes and no tissue/treatment interaction was identified. Only EP2 mRNA expression showed a significant effect of treatment. Dexamethasone-induced and spontaneous labor were associated with increased EP2 mRNA expression, considering all three tissues together. When considering the expression of FP mRNA between tissues, we found that the endometrium showed significantly higher expression than the placenta, which in turn, was higher than in the myometrium (P < 0.001). Levels of EP2 and EP3 mRNA expression were similar between the myometrium and endometrium, and both of these tissues had significantly higher expression of these genes than the placenta (P < 0.05). EP4 mRNA expression was highest in the endometrium followed by myometrium, and lowest in the placenta (P < 0.01).
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Myometrial Responsiveness to PGF2 and PGE2
PGF2 and PGE2 evoked concentration-dependent increases in tension in all tissues, both longitudinal and circular, with similar amplitudes attained from tissues collected before and during labor (Fig. 3, A and B, respectively). Consistent with the receptor expression data, the sensitivity of longitudinal myometrium to PGF2 was similar before and after labor onset (pD2 in Table 2, PGF2 subset, all strips). Tissue was obtained from the same animal before labor (during surgery for instrumentation) and subsequently during induced labor in a subset of five ewes. Again, maximum tension and sensitivity to PGF2 were not changed during labor (subset PGF2 in Table 2). There was also no difference in maximum tension development or sensitivity to PGF2 between tissues obtained during spontaneous labor versus dexamethasone-induced labor (TMAX 137% ± 10%, n = 4 vs. 139% ± 9%, n = 7; pD2 8.08 ± 0.53, n = 4 vs. 7.40 ± 0.44, n = 7).
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Similarly, in response to PGE2, there was no difference in maximum tension development or in tissue sensitivity between tissues obtained before versus during labor (Table 2, PGE2 subset). Also, there was no difference in response to PGE2 between longitudinal versus circular myometrium (Table 2, PGE2 subset). It is interesting to note that the sheep myometrium is approximately 10-fold more sensitive to PGE2 compared with its sensitivity to PGF2 (pD2 values in Table 2).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and PGE2 of the laboring and nonlaboring myometrial strips from the same animals. These observations suggest that the myometrium has already undergone any receptor expression changes that may occur by the time our observations were made (GA 137) and that no further increase in expression is required for effective labor. Consistent with this suggestion, Baguma-Nibasheka et al. [6] also found no difference in the response of nonlaboring versus laboring myometrium to exogenous PGF2. Our findings in the myometrium extend those of Gyomorey et al. [17] who reported no change in EP1–4 and FP mRNA expression assessed by in situ hybridization and reverse transcriptase-PCR with spontaneous labor. In contrast, Ma et al. [3] reported an increase in myometrial EP3, EP4, and FP expression with no change in EP2 mRNA expression at labor onset in sheep. However, both of these studies may have been complicated by the use of non-species-specific primers [3]. Our finding that myometrial EP2 mRNA expression was increased in spontaneous term labor was unexpected, and its significance is unclear. This is a receptor whose effect has been considered likely to reduce myometrial contractility, although our present observations are not consistent with this suggestion. EP1 mRNA expression was not detected in this or previous studies, suggesting that it does not play a significant role in mediating the effects of PGE2 in gestational tissues at labor onset.
The lack of increase in myometrial FP receptor expression does not discount the role of PGs in myometrial activation during labor or the possible use of PG receptor antagonists as therapeutic treatments of preterm labor. This is supported by our previous finding that the arterio-venous (AV) differences of PGF2 at the time of postmortem were increased by 2550% and 2100% in the dexamethasone-induced and spontaneous labor ewes, respectively. No change was found in the AV differences of PGE2 in either laboring group. Therapeutic agents may function by blocking the action of the ligands on PG receptors already present in the myometrium before labor onset. Indeed, we have recently used a specific, noncompetitive inhibitor of the FP receptor, THG 113.31, to suppress myometrial activity and delay RU486-induced labor in sheep [18].
The distribution of membrane-bound PG receptors has been reported to vary in the primate myometrium, with contractile receptors (FP and EP3) highest in the fundus and relaxatory EP2 receptors highest in the lower uterine segment [4]. In this study, we measured receptor expression and functional responses in the midsection of the uterus, thus we cannot exclude the possibility that differential changes in PG receptor expression may occur within the uterus.
Another significant finding of the present study was the increase in EP2 and EP3 mRNA expression in the placenta in association with labor and substantial expression of FP mRNA in the placenta throughout late gestation and labor. We [10, 11] and others [19] have demonstrated that the placentomes have the largest capacity for PG production in ovine gestational tissues at labor onset. At this time, the role of EP receptors in the placenta is unknown and it is also unclear whether PGE2 has a local action in the placentome via these receptors. To our knowledge, this is the first report of a changing pattern in PG receptor expression in ovine placentomes. Our findings suggest placental EP receptor up-regulation may influence or respond to mechanisms involved in the initiation of labor. The placental production of PGF2 rises rapidly before spontaneous and dexamethasone-induced labor in sheep [8, 10, 19], resulting from the combined effects of increased PGHS-2 and PGF synthase (PGFS) mRNA expression [11]. We believe that the resultant increase in placental PGF2 concentrations is largely responsible for the subsequent increase in uterine activity at labor onset, possibly via diffusion through the basal plate of the placentome to the adjacent myometrium. We speculate that placental PGF2 also acts locally within the placentome, possibly regulating vascular tone.
In endometrium, the expression of EP2 and EP4 mRNA increased with labor, potentially increasing the capability for stimulating adenylate cyclase and increasing cAMP formation. While the role of these changes in the endometrium is unknown, this increase in "relaxatory" cAMP-generating PG receptors may serve as a mechanism to regulate blood flow in these tissues at the time of labor. Further studies are required to investigate the localization of these receptors to determine whether they are present in the tissue cells or blood vessels.
The present finding of differences in the expression of PG receptor subtypes between myometrium, endometrium, and placenta suggests the existence of tissue-specific regulatory systems [3, 20] whose biological roles need to be identified. Overall, the placenta contained the lowest level of EP receptor expression, while the myometrium showed the lowest FP expression. Species differences also appear to exist in PG receptor expression. For example, myometrial EP2 mRNA expression decreases in baboons [21] and humans [9], and a previous report showed no change in sheep [17]. In contrast, we observed an increase in myometrial EP2 mRNA abundance following spontaneous labor compared with late gestation levels (137 days GA). This was not reflected in our functional studies, which showed no change in the sensitivity to PGE2. While the classical G protein-coupled PG receptors are localized on the plasma membrane, it has recently been demonstrated that PGs can activate intranuclear receptors, mediating their effects by altering gene transcription. Functional nuclear localized EP1, EP3, and EP4 of various subtypes have been found to affect intranuclear calcium transport and gene transcription [22, 23]. PGHS-2 has also been localized in the perinuclear region, thus locally generated PGs could activate nuclear EP receptors, thereby inducing gene transcription [24–26]. Further studies are required to determine the signal transduction mechanisms involved in the action of PGs on nuclear receptors and the role they may play in the labor mechanism.
In conclusion, we have simultaneously determined the expression of the receptor mRNA for the uterotonic PGs by quantitative real-time PCR in the key gestational tissues in association with both spontaneous and induced preterm labor using species-specific primers. We found no change in stimulatory FP receptor expression in the myometrium at labor onset, suggesting that receptor up-regulation does not contribute to the increasing uterine activity at this time. In keeping with this conclusion, the sensitivity of myometrial tissue to the uterotonic PGs was unaffected by the advent of labor. Overall, the results show that PG receptors in the myometrium are not up-regulated, as is seen with contraction-associated protein (CAP) genes in association with labor, suggesting their expressions are not controlled by the same mechanisms, nor do they fit the description of a CAP gene. We observed marked changes in the pattern of EP receptor expression in the placenta and endometrium. Further investigation of the potential role of these changes in the regulation of uterine function is required. We have shown in the same animals that the capacity to synthesize PGs increases markedly in the placentome and, to a lesser extent, the myometrium in association with labor. It therefore appears that PG synthesis, via the action of increased PGHS-2 and PGFS, is of greater importance than alterations in the expression of PG receptors in the uterotonic cascade at labor onset in sheep.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Hannah K. Palliser, Department of Physiology, Building 13F, Monash University, Victoria 3800, Australia. FAX 61 03 9905 2547; hannah.palliser{at}med.monash.edu.au
Received: 17 August 2004.
First decision: 21 September 2004.
Accepted: 7 December 2004.
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REFERENCES |
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from the ovine corpus luteum. Endocrinology 1995 136:3430-3436[Abstract]This article has been cited by other articles:
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) and during spontaneous and dexamethasone-induced labor (in labor, IL, 
)