Mol. Hum. Reprod. Advance Access originally published online on January 18, 2006
Molecular Human Reproduction 2005 11(12):859-864; doi:10.1093/molehr/gah228
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Prostanoid receptors in human uterine myocytes: the effect of reproductive state and stretch
1Imperial College Parturition Research Group, Department of Maternal Fetal Medicine, Imperial College School of Medicine, Chelsea and Westminster Hospital, London, UK, 2Department of Obstetrics & Gynecology, University of Cincinnati College of Medicine, Cincinnati, OH, USA and 3Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus, London, UK
4 To whom correspondence should be addressed at: Imperial College Parturition Research Group, Department of Maternal Fetal Medicine, Imperial College School of Medicine, Chelsea and Westminster Hospital, London, UK. E-mail: mark.johnson{at}imperial.ac.uk
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Abstract |
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In the human, prostanoids are known to be important mediators of uterine relaxation and contraction during pregnancy and parturition. We have previously shown that stretch of uterine smooth muscle cells increased prostaglandin H synthase 2 (PGHS-2) mRNA expression, PGHS-2 peptide synthesis and activity, however, the net effect on uterine contractility of this increase in prostaglandin synthesis would be determined by the expression of the different prostanoid receptors. Therefore, the aims of this study were to establish the expression of prostanoid receptor mRNA in uterine myocytes obtained from women in different reproductive states and to test the hypothesis that stretch of uterine myocytes alters prostanoid receptor mRNA expression to promote uterine contractility. Myocytes were isolated from women undergoing hysterectomy (NP) and pregnant women undergoing LSCS either before (NL) or after the onset of labour (L) and were subjected to 11% stretch for 1 h (n = 6 in all cases). Copy numbers of the individual receptors varied widely with reproductive state but followed the pattern: FP > IP = DP = EP-4 > TP = EP-3 = EP-2 > EP-1. FP mRNA expression was significantly lower in the NL group compared to the NP group and EP-3, EP-4 and TP mRNA expression was significantly lower in both NL and L groups compared to NP group levels. The level of mRNA expression of EP-1, EP-2, DP and IP did not differ between NP, NL and L groups. Stretch of cells derived from the NP group resulted in a significant decrease in EP-4 mRNA expression alone and of the NL group a significant decrease in EP-2 mRNA expression alone. Stretch had no effect on cells derived from the L group. These data show that pregnancy is associated with a significant reduction in 3 of 4 pro-contraction associated prostanoid receptor mRNA expression and 1 of 4 pro-relaxant. Stretch elicited no consistent change in prostanoid receptor mRNA expression.
Key words: pregnancy/prostanoid receptors/stretch/uterine smooth muscle cells
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Introduction |
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During pregnancy, prostaglandins have a critical role in determining the balance between uterine contraction and relaxation. Increased prostaglandin activity in reproductive tissues is one of the most consistent findings with parturition across species and is held to be of particular importance in human term and preterm (Gibb, 1998
; Challis et al., 2000, 2002; Lindstrom and Bennett, 2004). The biological effects of prostanoids are mediated through eight specific, pharmacologically distinct receptors which can be broadly divided into two groups based on their effects on smooth muscle cells: a relaxant group (DP, EP-2, EP-4, IP) which act by increasing intracellular levels of cAMP and a contractile group (EP-1, EP-3, FP, TP) which act by decreasing intracellular cAMP or increasing intracellular calcium levels (Coleman et al., 1994). Previous studies on the prostanoid receptor expression in myometrium have been performed in animals (Matsumoto et al., 1997; Brodt-Eppley and Myatt, 1998; Smith et al., 1998, 2001; Ma et al., 1999; Ou et al., 2000; Al-Matubsi et al., 2001) and in the human (Senior et al., 1993; Matsumoto et al., 1997; Brodt-Eppley and Myatt, 1999; Erkinheimo et al., 2000; Goharkhay et al., 2002; Wing et al., 2002; Astle et al., 2005). In general, these studies have focused on pregnant myometrium, and only the mRNA expression of selected prostanoid receptors in whole tissue has been described. Leonhardt et al. studied the expression of the receptors for PGE2 (EP-1, EP-2, EP-3, EP-4), PGF2
(FP), prostacyclin (IP) and thromboxane A2 (TP) in human pregnant myometrium by RT–PCR, in situ hybridization and immunohistochemistry (Leonhardt et al., 2003). Myometrial tissue was obtained from women at term not in labour and from women who delivered preterm. In these samples EP-1, EP-2, EP-3, EP-4, FP, TP and IP receptor mRNA and protein were found to be present (Leonhardt et al., 2003). More recently, the distribution of EP1–4 and the splice variants of EP-3 were studied in upper and lower segment of the human uterus by RT–PCR and immunohistochemistry (Astle et al., 2005). They found that EP-1 mRNA expression was significantly increased in the lower segment with labour, EP-3 reduced and EP-2 and -4 unaltered (Astle et al., 2005). One previous study, using Northern blot analysis reported that human uterine smooth muscle cells expressed EP-2 mRNA, but that the expression of EP-1, EP-3, EP-4, FP and IP mRNA was low or below the limit of detection (Erkinheimo et al., 2000), no other studies to date have examined the expression of prostanoid receptors in isolated myometrial smooth muscle cells.
During human pregnancy, excessive uterine stretch, as seen in multiple pregnancy, polyhydramnios or pregnancy in a unicornuate uterus, is associated with an increased risk of preterm labour. In animal studies, stretch increases the expression of myometrial contraction-associated proteins (Ou et al., 1997, 1998; Wu et al., 1999; Parry and Bathgate, 2000). In particular, PGHS-2 was differentially increased in the pregnant horn of the sheep uterus with the onset of labour (Wu et al., 1999). Further in the human, artificially stretching the uterine cavity by the insertion and inflation of a balloon can induce abortion, labour (Manabe et al., 1981, 1982) and at 3 days post-partum result in uterine contractions (Manabe et al., 1983). Recently, we have shown that stretch of human uterine myocytes in vitro increases PGHS-2, IL-8 and OTR mRNA expression (Loudon et al., 2004; Sooranna et al., 2004; Terzidou et al., 2005). The increase in PGHS-2 mRNA expression was associated with increased PGHS-2 protein synthesis and the levels of PGE2 and PGI2, but a reduction in PGF2 in the supernatant. However, the net effect of this increase in prostaglandin synthesis would be determined by the relative expression of the different prostanoid receptors. Therefore, the aims of this study were to establish the expression of prostanoid receptor mRNA in uterine myocytes obtained from women in different reproductive states and to test the hypothesis that stretch of uterine myocytes can alter prostanoid receptor mRNA expression to promote uterine contractility.
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Tissue specimens
Biopsies (0.5 x 0.5 cm3) of term human myometrium were collected at the time of caesarean section (LSCS) from women not in labour (NL, n = 6), during active labour (L, n = 6) and from hysterectomy (NP, n = 6) in Dulbecco’s modified Eagle’s medium (DMEM) containing 100 m units/mL penicillin and 100 µg/mL streptomycin. The indications for LSCS in labour group were slow labour, fetal distress and breech presentation, and in the non-labour group, previous LSCS, breech presentation and maternal request. Samples were removed from the upper margin of the lower segment incision. The indications for hysterectomy were menorrhagia and prolapse, samples were removed from the lower anterior aspect of the uterus. Samples were stored at 4°C for no more than 3 h before cell preparation for culture. Mean maternal age [NL = 31 (26–37) years; L = 30 (27–40) years and NP = 42 (39–47) median range]. Gestational age [NL = 39 (38 + 3 – 39 + 2) and L = 38 + 5 (37 – 40 + 4) weeks] did not differ significantly. The indications for LSCS in labour group were slow labour, fetal distress and breech presentation, and in the non-labour group, previous LSCS, breech presentation and maternal request. All specimens were obtained after patient consent, and the Riverside Research Ethics Committee approved the study.
Cell culture
Primary human uterine myocytes were isolated using a mixture of collagenases and cultured in DMEM medium 7.5% fetal calf serum, 100 m units/mL penicillin and 100 g/mL streptomycin in T75 in an atmosphere of 5% CO2: 95% air at 37°C (Pieber et al., 2001). Myometrial cells grown in this manner have previously been characterized (Pieber et al., 2001). Cells from passage 1–4 were trypsinized in 0.25% trypsin containing 0.02% EDTA in phosphate-buffered saline (PBS) and cultured in 6 well flexible-bottomed culture plates precoated with collagen type I in 3 mL of DMEM medium. When cells were 85–95% confluent (days 3–4), old medium was removed and replaced with 3 mL of fresh medium supplemented with 7.5 mM HEPES but only 1% fetal calf serum (FCS) overnight. After 16 h, these were subjected to a static stretch of 11% for 1 h using a flexercell strain unit (Flexcell International, McKeesport, PA, USA). One hour stretch at 11% was chosen as we have previously compared different degrees and duration of stretch and found, in terms of RNA analysis, that this gives the most consistent results. Unstretched cells grown and treated similarly were used as controls. More than 99% of cells remained attached to the 6 well culture plates after stretch protocols, and these cells were frozen in liquid nitrogen and stored at –80°C for extraction of RNA. Stretch may be constant, as might be expected during pregnancy, or episodic, as at the time of labour. In these studies, we have modelled stretch during pregnancy and consequently have used constant rather than episodic stretch.
Quantitative RT–PCR
Total RNA was extracted and purified from myometrial cells grown in 6 well flexible-bottomed culture plates using an RNeasy mini kit from Qiagen (Crawley, West Sussex, UK). After quantification 1.0 µg was reverse transcribed with oligo dT random primers using MuLV reverse transcriptase (Applied Biosystems, Warrington, Cheshire, UK). Paired oligonucleotide primers for amplification of human prostanoid receptors were designed using Primer Designer (Scientific and Educational Software, Durham, NC, USA) against the sequence downloaded from GenBank. The primer sets used (Table I) produced amplicons of the expected size and flanked intron/exon junctions. Assays were validated for all primer sets by confirming that single amplicons of appropriate size and sequence were generated. Quantitative PCR was performed in the presence of SYBR Green (Qiagen), and amplicon yield was monitored during cycling in a RotorGene Sequence Detector (Corbett Research, Mortlake, Sydney, Australia) that continually measures fluorescence caused by the binding of the dye to double-stranded DNA. Pre-PCR cycle was 10 min at 95°C followed by up to 45 cycles of 95°C for 20 sec, 58–60°C for 20 s and 72°C for 20 s followed by an extension at 72°C for 15 s. The final procedure involves a melt over the temperature range of 72–99°C rising by 1 degree steps with a wait for 15 s on the first step followed by a wait of 5 s for each subsequent step. The cycle at which the fluorescence reached a preset threshold (cycle threshold) was used for quantitative analyses. The cycle threshold in each assay was set at a level where the exponential increase in amplicon abundance was approximately parallel between all samples. All mRNA abundance data were expressed relative to the amount of the constitutively expressed glyceraldehyde-3-phosphatedehydrogenase (GAPDH). The r2 value for each curve and efficiency of each primer pair is summarized in Table I.
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Conventional PCR was performed using Ampli-Taq Gold DNA polymerase (Applied Biosystems). Pre-PCR cycle was 10 min at 95°C followed by 35 cycles of 95°C for 1 min, 56–60°C for 1 min and 72°C for 1 min followed by final extension 72°C for 10 min.
Statistical analysis
Differences between prostanoid receptor : GAPDH mRNA ratios by reproductive state were analysed by unpaired two-tailed t-tests and between unstretched and stretched cells by paired two-tailed t-tests. Kolmogorov-Smirnov and Shapiro-Wilk statistics were used to determine normality of each sample pairs. Differences were considered statistically significant at P > 0.05.
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Results |
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Uterine myocytes in culture expressed all eight prostanoid receptor mRNA, although the copy numbers varied widely. The distribution of the receptors was similar in cells isolated from NP, NL and L myometrium. Expression of FP was highest and EP-1 lowest, with FP > IP = DP = EP-4 > TP = EP-3 = EP-2 > EP-1 when calculated as a ratio to GAPDH values.
The level of mRNA expression of EP-1, EP-2, DP and IP did not differ between NP, NL and L groups, whereas FP (P = 0.027) mRNA expression was significantly lower in the NL group compared to the NP group and EP-3 (P = 0.008 and 0.006), EP-4 (P = 0.0007 and 0.019) and TP (P = 0.002 and 0.004) mRNA expression was significantly lower in both NL and L groups compared to NP group levels. These data show that pregnancy is associated with a significant reduction in expression of the mRNA of 3 of 4 pro-contraction-associated prostanoid receptors mRNA and 1 of 4 pro-relaxant. Only in the case of FP was this reduction partially reversed in the cells derived from the L group (Figure 1a and b).
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Stretch of cells derived from the NP group resulted in a generalized reduction in expression of prostanoid receptor mRNA with the exception of EP-2, in the NL cells, stretch elicited a mixed response and in the L cells an increase in all prostanoid receptor mRNA (Figure 2a–c). In the NP group, EP-4 and in the NL group, EP-2 mRNA expression was significantly reduced by stretch (P = 0.19 and 0.016, respectively; Figure 2a and b). Stretch had no significant effects in the L group (Figure 2c).
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Discussion |
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These data show that all eight prostanoid receptor mRNA are expressed in human uterine smooth muscle cells and that pregnancy is associated with a reduction in expression of the pro-contraction prostanoid receptors EP-3, FP and TP and of the pro-relaxant EP-4, consistent with a pro-relaxant state as has been suggested by Matsumoto (Matsumoto et al., 1997
). Stretch has no consistent effect on prostanoid receptor expression.
In terms of the EP receptor subtype mRNA expression, we found that EP-4 was the most abundant followed by EP-3, EP-2 and EP-1. These data contrast with those of Leonhardt et al. who found smooth muscle localization of EP-1, -2 and -4 but not EP-3 by in-situ hybridization and immunohistochemistry, (Leonhardt et al., 2003) and those of Erkinheimo et al. who found higher expression of EP-2 than the other EP subtypes in uterine myocyte cultures (Erkinheimo et al., 2000). EP-4 was detectable, but at low levels that were increased by IL-1ß (Erkinheimo et al., 2000). Astle et al. using immunohistochemistry found in myometrial smooth muscle cells that EP-1 was relatively the most abundant, followed by EP-2 and EP-4, while EP-3 was present in low levels, however, given that EP-3 has nine spliced variants, the antibody specificity may vary and so contribute to the differences observed (Astle et al., 2005). In terms of reproductive state, we found that EP-3 and EP-4 mRNA were reduced in pregnancy, and EP-1 and EP-2 were unchanged. Astle et al. found in lower segment samples increased EP-1 mRNA expression with labour (L > NP and NL), a reduction in EP-3 mRNA expression with labour (NP and NL > L) and no change in either EP-2 or EP-4 by reproductive state. Our data are not dissimilar for EP-2 and EP-3 mRNA expression, but differ in that we found no differences in EP-1 mRNA expression by reproductive state and a reduction in EP-4 mRNA expression (NP> NL and L). Again, these differences may reflect our use of smooth muscle cells compared to whole tissue and our use of quantitative PCR as opposed to the semi-quantitative PCR used by Astle et al. In addition, our studies were performed on primary cells in culture, and this may have influenced receptor mRNA expression. In the case of EP-1, the differences are more difficult to explain. In Astle et al.’s study, EP-1 was strongly localized to the smooth muscle cells by immunohistochemistry and relatively less was found in other components of the myometrium, thus changes in EP-1 mRNA are likely to reflect changes in EP-1 mRNA in smooth muscle cells. The animal data are limited in terms of a comparison between non-pregnant and pregnant, in the rat EP-2 mRNA expression is increased during pregnancy but declined with the onset of labour (EP-2 mRNA was unchanged in both our study and that of Astle et al.; Dong et al., 2000). In the baboon, EP-2 mRNA expression (assessed by northern analysis) declined with the onset of labour, and no change was noted in EP-1, EP-3 and EP-4 mRNA expression (Smith et al., 2001). In the sheep, again assessed using northern analysis, there was no change in EP-2 and an increase in EP-4 mRNA expression with labour (Ma et al., 1999). The animal data are not strictly comparable as they are based on whole tissue analysis in samples obtained from the equivalent of the uterine body. That being said, both the baboon and sheep data are similar to our own and show neither a consistent up-regulation of pro-contraction nor a down regulation of pro-relaxant EP receptor mRNA with the onset of labour.
We found a reduction in FP mRNA expression in pregnancy that was partially reversed with the onset of labour, consistent with the pro-relaxation during pregnancy and pro-contraction with the onset of labour. Our data agree with those of others studying whole myometrium who found that FP mRNA decreased during pregnancy and increased with labour (Matsumoto et al., 1997; Brodt-Eppley and Myatt, 1999). The animal data are contradictory; in the baboon, uterine FP expression does not change with the onset of labour (Smith et al., 2001), in the mouse, rat and sheep its expression is increased with the onset of labour (Ma et al., 1999; Cook et al., 2000; Dong and Yallampalli, 2000; Al-Matubsi et al., 2001).
Studies of TP, DP and IP are limited. Our data show a reduction in expression of TP during pregnancy which is unaltered with the onset of labour. The expression of DP and IP are unchanged in different reproductive states. No studies have investigated the mRNA expression of these receptors in different reproductive states, however, TP mRNA has been found in human myometrium (Swanson et al., 1992), as has IP mRNA albeit at low levels (Erkinheimo et al., 2000), DP mRNA was undetectable in one study (Leonhardt et al., 2003). In animal studies, IP and TP mRNA have been reported to be present in baboon myometrium (Smith et al., 2001), there are no data with regard to the expression of TP, IP or DP in the rat, mouse or sheep. Our observation of a reduction in TP mRNA expression is consistent with uterine quiescence of pregnancy.
Stretch of human uterine myocytes had no consistent effect on prostanoid receptor expression. Previous studies in the human have compared the expression of EP-1, -3 and -4 in twin and singleton pregnancies and found no difference (Lyall et al., 2002). Two studies in the rat have concluded that stretch has no effect on FP mRNA expression (Lintner et al., 1986; Ou et al., 2000) and that it seems that FP expression is regulated by estrogen and progesterone in the rat (Dong and Yallampalli, 2000; Ou et al., 2000). In our previous study, we reported that mechanical stretch of human uterine myocytes in vitro resulted in an increase in PGHS-2 expression, PGHS-2 protein and increased PGE2 and PGI2 and decreased PGF2 synthesis (Sooranna et al., 2004). Taken with these data, it seems that stretch in terms of the prostaglandin system is likely to be pro-relaxant. However, the insertion and inflation of a balloon into the uterine cavity 3 days post-partum is associated with increased uterine contractions which can be blocked by the administration of indomethacin, suggesting that stretch in vivo is pro-contractant and that this is mediated via increased prostaglandin production (Manabe et al., 1983). Equally, post-partum events may alter the responses to stretch, and our work has been performed on pregnant uterine myocytes before and during labour.
These data show that pregnancy is associated with a reduction in 3 of 4 pro-contractile prostaglandin receptor mRNA. This suggests that during pregnancy the contractile prostaglandin system is down-regulated favouring myometrial quiescence. This is partially reversed in the case of FP mRNA levels with the onset of labour. We also show that primary cultures of uterine smooth muscle cells are a useful model to study the effect of stretch on PG receptor mRNA expression.
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Acknowledgements |
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This work was supported by grants from Wellbeing and the Barclay Foundation.
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References |
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Submitted on June 9, 2005; revised on August 8, 2005; accepted on August 18, 2005
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