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Regular Article |
a Laboratory for Pregnancy and Newborn Research, Department of Physiology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853
ABSTRACT
We determined the effect of gestational age and labor on the regional expression of prostanoid receptor genes in baboon myometrium. Cesarean hysterectomy was performed on 15 pregnant baboons of known gestational age in the last third of pregnancy, five of them during spontaneous term labor. Expression of prostanoid receptor genes was studied using Northern blot analysis. Transcripts of similar size to the human were detected for prostanoid EP1, EP2, EP3, EP4, IP, FP, and TP receptor genes using Northern blot analysis. There were no gestational age-related changes in expression of these genes. Expression of EP1, EP3, and IP receptor RNA mRNA was significantly higher in myometrium from the fundus (compared with the lower segment), whereas EP2 gene expression was significantly lower in the fundus. Labor was associated with a reduction in the regional variation of both EP2 and IP receptor gene expression, but not EP1 and EP3 expression. Labor was also associated with an overall lower level of expression of EP2 receptor mRNA. We conclude that regional and labor-related variation in myometrial expression of prostanoid receptor genes may have a key role in primate parturition.
gene regulation, hormone action, parturition, pregnancy, prostaglandins, signal transduction, uterus
INTRODUCTION
Prostaglandins (PGs), PGE2 and PGF2
in particular, are believed to have a key role in the initiation of parturition in many species, including humans [1]. Much of the research on the potential role of PGs in regulating the onset of labor has focused on the factors determining PG concentrations; specifically, the balance of PGH synthase (PGHS) and PG dehydrogenase (PGDH) activities in key intrauterine tissues [2–4]. However, it is evident from the human clinical use of exogenous synthetic PGs to induce labor that the response to a standard dose of PGE2 is highly variable between women, from virtually no effect, to excessive stimulation necessitating immediate delivery by cesarean method [5]. This observation suggests that the sensitivity of the uterus to PGs may be a factor controlling myometrial contractility at term.
The family of receptors mediating the effects of PGs has now been well characterized, and an initial functional classification has been validated by molecular biology [6]. There are five currently recognized G-protein-coupled prostanoid receptor types, encoded by separate genes (or a family of genes in the case of EP receptors) and named according to the PG that is the most potent agonist: EP (PGE2), DP (PGD2), FP (PGF2), IP (PGI2), and TP (thromboxane) [7]. In addition, there are at least four subtypes of EP receptor (numbers 1 to 4), encoded by separate genes. The EP2 and EP4 receptors are positively coupled to adenylate cyclase (AC) [8], the EP1 receptor is coupled to calcium influx [9], and the EP3 receptor is generally negatively coupled to AC [10]. Consequently, EP2 and EP4 receptor activation inhibits smooth muscle contractility [11, 12], whereas EP1 and EP3 activation promotes contraction [11].
Given that there are multiple subtypes of prostanoid receptors present in the uterus and that these receptors mediate opposing effects on myometrial contractility, we hypothesize that variation in the expression of prostanoid receptors may have an important physiological role in the control of myometrial contractility during parturition. Previous studies of prostanoid receptor gene expression in labor are limited to nonprimate species [13, 14] and a study of lower-segment biopsies from pregnant women [15]. In the present study we quantified the expression of prostanoid receptor genes in baboon myometrium, from both the lower segment and the fundus, obtained from 15 animals in the last third of pregnancy, five of which were in spontaneous labor.
MATERIALS AND METHODS
Animal Methods
Animal methods and surgical procedures have been described previously [16]. Pregnant baboons were obtained from the Southwest Foundation for Biomedical Research, San Antonio, Texas. They had been harem-mated and gestational age was confirmed by early ultrasound. Total cesarean hysterectomy was performed under general anesthesia (ketamine induction, halothane maintenance). Postsurgical analgesia was maintained with intra-arterial butorphanol (0.3 mg/kg/day). Samples of myometrium were obtained from the fundus and lower segment, flash-frozen in liquid nitrogen, and stored at -80°C until use. The lower segment was defined as the 1-cm portion of the uterus immediately superior to the internal os of the cervix. The fundus was defined as the portion of the uterine wall superior to the upper limit of the uterine cavity.
Ten animals were not in labor and in the last third of pregnancy at the following days gestational age (dGA): 121, 128, 141, 153, 159, 162, 162, 177, 177, 180 (term = 180–185 days). The cervix was uneffaced and closed in all of these animals. Uterine electromyogram (EMG) leads had been sited in three of these animals going close to term (the animals delivered after 170 dGA). Analysis of EMG traces of the 48 h preceding surgery revealed that myometrial activity was solely in the contractures mode with no contraction activity. No drugs of any form had been administered to any of the animals in the 2 wk preceding surgery. Cesarean hysterectomy was also performed on five animals in spontaneous labor. Of these, four had EMG electrodes sited. These animals had a baseline cervical examination at the time of their first EMG contraction activity and were re-examined when they had a sustained switch from contractures to contractions (>30 min). The gestational ages at hysterectomy were 164, 184, 191, and 193. The cervical dilations for these animals were 6, 3, 3, and 2 cm, respectively (the cervix was closed in all four at baseline examination). In a fifth animal without EMG electrodes, cesarean delivery was performed at 172 dGA and at the time of the procedure it was found that the cervix was 4 cm dilated, fully effaced, and a hysterectomy was performed.
All procedures were approved by the Cornell University Institutional Animal Care and Use Committee and the facilities were approved by the American Association for the Accreditation of Laboratory Animal Care. The experiments were conducted in accordance with the Guide for Care and Use of Laboratory Animals (National Academy of Sciences, 1996).
Northern Analysis
Polyadenylated RNA was extracted from frozen tissue by oligo dT cellulose-affinity chromatography using a commercial kit (Fast Track 2.0, Invitrogen, San Diego CA). Samples of polyadenylated RNA were denatured in 17.4% (vol/vol) formaldehyde, 50% (vol/vol) freshly deionized formamide, 20 mM MOPS (3-[N-morpholino] propanesulfonic acid), 5 mM sodium acetate, and 1 mM EDTA pH 7.0 for 5 min at 65°C and separated by electrophoresis on a 1.4% (wt/vol) agarose 0.66 M formaldehyde gel. The gel was visualized under UV transillumination and photographed to determine the distance of migration of a series of standard RNA markers (Gibco, Rockville, MD). The RNA was transferred onto a nylon membrane (Gene Screen plus, NEN; Dupont, Wilmington, DE) by capillary blotting for 24 h in 10x saline-sodium citrate (SSC; 1x SSC is 0.15 M NaCl and 0.015 M sodium citrate pH 7.0). Prehybridization (>1 h) and hybridization (>18 h) were carried out in hybridization bottles in an oven at 65°C when using riboprobes and 45°C in sealed bags when a cDNA probe was used. A commercial 50% formamide-based hybridization buffer was employed (Northern Max or UltraHyb; Ambion, Austin, TX). The probe concentration was approximately 1 x 106 cpm per milliliter of hybridization buffer. Membranes were washed twice for 5 min in 2x SSC and 0.1% SDS at 65°C and twice for 1 h in 0.1x SSC and 0.1% SDS at 65°C when riboprobes were employed and were washed in the same buffers but at 45°C when cDNA probes were employed. Kodak X-Omat film was exposed to the membrane with an intensifying screen at -80°C. After probing for the receptor gene of interest, membranes were stripped (see below) and reprobed for housekeeping genes (see below).
Synthesis of Probes
The EP1, EP2, EP3, EP4, DP, FP, and IP prostanoid receptor cDNAs had been cloned into either the pcDNA3 or pcDNAIamp vectors (both Invitrogen), which include promoters for phage polymerases SP-6 and T-7. The plasmid was linearized by an appropriate restriction enzyme and antisense riboprobes were synthesized using a commercial kit (StripEZ RNA, Ambion) labeled with [-32P] UTP (800 Ci/mmol; NEN Life Science, Boston, MA). Template DNA was removed by addition of 2 units of RNase-free DNase and incubation for 15 min at 37°C. Random-primed cDNA probes were used where riboprobes could not be synthesized and the inserts were labeled with [-32P]deoxy-CTP (3000 Ci/mmol) using the random priming method (StripEZ DNA; Ambion, TX) to specific activities of approximately 1 x 109 cpm/µg. Both DNA and RNA probes was separated from unincorporated nucleotide using a spin column (Probe Quant G-50, Pharmacia Amersham, Piscataway, NJ) and quantified. Probes were stripped from Northern membranes using the manufacturer's protocol (StripEZ RNA and StripEZ DNA; both Ambion, TX) and membranes were consecutively stripped and reprobed to each of three housekeeping genes.
The human EP2 receptor cDNA was obtained from Dr. D.F. Woodward of Allergen, Irvine, California. The human prostanoid receptor DP, EP3, EP4, IP, and FP cDNAs were obtained from Dr. Mark Abramovitz of Merck Frosst, P.O. Box 1005, Quebec H9R 4P8, Canada. The human TP receptor cDNA was obtained from Oxford Biomedical (Oxford, MI) and the mouse EP1 receptor cDNA was obtained from Dr. Y. Sugimoto of Kyoto University, Japan. The plasmids (all TRIscript, Ambion) containing the glyceraldehyde-3-phosphate dehydrogenase (GAPDH), beta-actin, and cyclophilin cDNAs with RNA polymerase promoters were purchased from Ambion.
Statistical Analysis
The estimated size of transcripts was calculated by fitting a curve (using Graph Pad Prism, version 3.0; Graph Pad Software, San Diego, CA) to the graph of distance of migration plotted against molecular weight of the markers. The size of autoradiographic signals was quantified using densitometry. When multiple bands were observed, the bank with the strongest signal is displayed graphically, although all signals that clearly exceeded background and could be reliably quantified were analyzed densitometrically. The expression of a given prostanoid receptor gene was expressed as a ratio to each of three housekeeping genes, GAPDH, beta-actin, and cyclophilin. All numerical data were summarized as the mean and SEM. Correlation was determined using both simple linear regression and using Spearman's rho. Because samples were obtained from the lower uterine segment and fundus of the same animals, variation in the level of expression was determined using repeated measures ANOVA. Adjusting comparisons for gestational age was performed using analysis of covariance. Statistical analysis was performed using Stata, version 6.0 for Windows. Statistical significance was assumed at the 5% level.
RESULTS
Clear signals of similar molecular weight to the cloned human prostanoid receptor genes were detected in myometrium for the EP1, EP2, EP3, EP4, FP, IP, and TP receptors genes, both from the lower segment and uterine fundus and from animals in labor and not in labor (Figs. 1 and 2). All blots were stripped and reprobed for each of three housekeeping genes: GAPDH, beta-actin, and cyclophilin (Fig. 3).
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Densitometric analysis of all signals (expressed as a ratio to beta-actin) failed to demonstrate any significant association between gene expression and gestational age among animals not in labor (all P > 0.05, Pearson and Spearman correlation coefficients).
Densitometric analysis of expression of EP receptor subtypes (relative to beta actin, Fig. 4) demonstrated an overall lower level of expression of the EP2 receptor in myometrium from animals in labor. Expression of the EP1 and EP3 receptor genes was higher in the fundus compared with the lower segment, whereas expression of the EP2 receptor gene was higher in the lower segment. Labor diminished the magnitude of the difference between the fundus and lower segment for EP2 gene expression, but not EP1 and EP3 receptor expression (Fig. 4). In addition to the 2.6-kilobase (kb) EP3 signal presented graphically, the 7.7-kb and 5.5-kb signals were also quantified. When expressed as a ratio to beta-actin, there was a significant difference in the level of these signals comparing the lower segment and fundus (P = 0.009 and P = 0.03, respectively) but there was no significant difference comparing labor and not in labor (P = 0.90 and P = 0.78, respectively) and there was no significant interaction between labor and uterine site (P = 0.66 and P = 0.18, respectively).
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Densitometric analysis of non-EP receptor types (relative to beta actin, Fig. 5) demonstrated no overall change in the level of expression of these genes in association with labor. However, IP receptor expression was higher in the fundus (compared with the lower segment) although the difference was diminished in animals in labor (Fig. 5). In addition to the 2.0-kb IP receptor gene signal presented graphically, the 4.0-kb and 2.7-kb signals were also quantified. When expressed as a ratio to beta-actin, there was no significant difference in the level of these signals comparing the lower segment and fundus (P = 0.15 and P = 0.40, respectively), there was no significant difference comparing labor and not in labor (P = 0.46 and P = 0.96, respectively) but there was a significant interaction between labor and uterine site for the 2.7-kb transcript (P = 0.04) but not the 4.0-kb transcript (P = 0.12). The pattern of change in expression of the 2.7-kb transcript was similar to the 2.0-kb transcript (i.e., an increase in expression in the lower segment comparing not in labor [mean in arbitrary units {SEM} (0.47 {0.15}) and labor (0.74 {0.09}) but no increase in the fundus (0.64 {0.12} and 0.38 {0.10}, respectively). In addition to the 2.2-kb TP receptor gene signal, the 2.8-kb signal was quantified. There was no significant variation in the expression of this gene relative to beta actin with respect to labor or uterine site (all P > 0.05).
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Given the wide scatter of gestational ages of animals in labor (164–193 dGA), we used analysis of covariance to test the hypothesis that the effect of labor may have varied according to gestational age. There was no statistically significant interaction between gestational age and labor for any of the signals (all P > 0.05).
The ratio of the EP2 receptor gene signal to the EP3 receptor gene (2.6 kb) signal was greater in the fundus than in the lower segment, decreased overall in association with labor, and the magnitude of the difference between the lower segment and fundus was diminished in labor, although a significant difference persisted in labor (Fig. 6).
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All but one of the comparisons that were statistically significant with beta-actin were also significant when the signal was expressed as a ratio to GAPDH or cyclophilin. The exception was comparison of the 2.0-kb IP receptor signal between the lower segment and fundus. This was significant at P = 0.02 and 0.0004 with beta-actin and cyclophilin, respectively, but the P value was 0.15 when related to GAPDH.
DISCUSSION
The most striking observation of the present study was that labor was associated with a much lower level of expression of the inhibitory prostanoid EP2 receptor and this was observed both in the fundus and lower segment. Studies of isolated strips of human myometrium have demonstrated a profound inhibitory effect of EP2 agonists on contractility and a profound excitatory effect of EP3 receptor activation [11]. Reduced expression of EP2 receptors would be anticipated to increase the stimulatory effect of a given concentration of PGE2 on the myometrium acting through EP1 and EP3 receptors and, therefore, promote the process of parturition. We hypothesize, therefore, that reduced expression of the inhibitory EP2 receptor in primate myometrium may have a key role in promoting myometrial contraction during labor. If confirmed in the human, this suggests that an EP2 receptor antagonist may have a role in the induction of labor and that an EP2 receptor agonist may have a role in the treatment or prophylaxis of premature labor, although the effect of such a drug may be diminished in active labor due to loss of EP2 receptor expression.
We confirmed our previous observation [17] of regional differences in EP2 and EP3 receptor gene expression comparing lower segment and fundus, and that these differences were maintained in labor. It is interesting that the magnitude of the difference in EP2 receptor gene expression between the lower segment and fundus was significantly diminished by labor, although a difference persisted. By optimizing our techniques, we could also detect EP1, TP, and IP receptor gene expression using Northern analysis. These studies demonstrated regional variation in both the EP1 and IP receptor genes. In the case of the EP1 receptor gene, expression was greater in the fundus than in the lower segment, but labor had no statistically significant effect on either the absolute level of expression or the difference between the two regions. However, the magnitude of the difference in the level of EP1 expression comparing the two regions was relatively modest. In the case of the IP receptor gene, expression was lower in the lower segment before labor, but not in tissue obtained during labor. The higher level of expression of the excitatory EP1 is consistent with our previous observation that strips of myometrium from the fundus exhibited a greater contractile response to PGE2 than strips from the lower segment [17]. Given that the gradient in the level of expression of the EP1, EP2, and EP3 receptor genes of the animals persisted in labor, we hypothesize that differential expression of prostanoid EP receptor subtypes may have a role in the relative relaxation of the lower segment in labor. The greater level of expression of the inhibitory IP receptor in the lower segment during labor suggests that PGI2 may also have a role in this process, which is consistent with the inhibitory effect of PGI2 on isolated strips of human lower segment myometrium [11]. However, the current studies were confined to analysis of mRNA and these conclusions assume parallels in the level of mRNA and functional receptors.
Relating the current observations to previous studies, there are interesting parallels and differences. Reduced expression of EP2 receptor mRNA in myometrium in association with labor has now been demonstrated in the baboon (present study) and the rat [13], and in association with advancing gestational age in the human [15]. However, there is no significant change in EP2 receptor gene expression in ovine myometrium in pregnancy [14]. This species difference in genetic expression is paralleled by functional differences in response of myometrial strips because both human [11] and baboon myometrium [18] relax in response to EP2 receptor agonists, whereas these drugs are without effect in ovine myometrium [18, 19]. We have also demonstrated reduced EP2 receptor gene expression in the baboon cervix and decidua in association with labor, which suggests that this receptor may have a key role in the control of parturition [20].
The lack of an effect of labor on expression of the FP receptor gene differs from studies using human lower uterine segment using polymerase chain reaction, which demonstrated increased FP receptor mRNA in biopsies taken from women in labor at the time of cesarean delivery, as well as animal studies in the rat [13] and sheep [14]. The contractile response to PGF2 and expression of FP receptor mRNA is the same in myometrial strips from the lower segment and fundus of baboons [17]. We interpreted this observation as possibly indicating a role for the FP receptor in postpartum contraction of the uterus, which is consistent with the efficacy of FP agonists in the management of refractory atonic postpartum hemorrhage [21]. It is possible, therefore, that expression of FP receptor mRNA could increase in the final stages of labor, and that the time of sampling of myometrium with respect to the total duration of labor may explain this difference.
The size of transcripts observed in the present study was similar to previous reports of Northern blots from the human. As in previous studies in the human, multiple bands were present using the EP3 [22], IP [23], and TP probe [24], whereas discrete bands were observed using the EP1 [9], EP2 [8], EP4 [25], and FP [26] probes. Furthermore, the estimated size of transcripts was similar to these reports of Northern analysis of human RNA. Such variation as was observed (less than 20%) may be related to variation in untranslated regions of the gene, which has been previously inferred by the discrepancy between the size of the full-length cDNA and the size of transcripts in Northern analysis [27] as well as inevitable variation due to experimental error.
The foregoing assumes that there is a correlation between expression of the gene encoding the receptor and the amount of functional receptor present. This assumption is supported by our previous work in myometrium that demonstrated parallels between regional variation in the contractile response to PGs and the expression of genes encoding prostanoid receptor genes in baboon myometrium [17]. Further studies using other techniques such as radioligand binding or Western blot analysis are warranted, but are currently problematic due to technical limitations. Radioligand binding is limited due to the lack of truly selective ligands [28], a problem underlined by studies using cells expressing recombinant prostanoid receptors that have demonstrated that many ligands that are supposed to be highly selective for a given receptor or receptor subtype bind extensively to other receptors [29]. The use of Western blot analysis is limited by the fact that antibodies for all the receptor types and subtypes are not yet widely available.
Further studies should also address the control of expression of the EP2 receptor gene. There is currently very little information on the transcriptional regulation of prostanoid receptor genes. Elucidation of the factors that control expression of this gene in primate myometrium may shed light on the molecular pathways controlling primate parturition.
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FOOTNOTES
First decision: 15 August 2000.
1 Supported by grant HD 21350 from the National Institutes of Health. G.C.S.S. was supported by the Wellcome Trust. 
2 Correspondence: Gordon C.S. Smith, University of Glasgow, Department of Obstetrics and Gynaecology, The Queen Mother's Hospital, Yorkhill, Glasgow, G3 8SH, United Kingdom. FAX: 44 141 357 3610; gcs4{at}cornell.edu
Accepted: November 15, 2000.
Received: July 17, 2000.
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