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Laboratory for Pregnancy and Newborn Research, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853; and University of Glasgow, Department of Obstetrics and Gynecology, Royal Infirmary, Glasgow G31 2ER, United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study was designed to characterize prostaglandin dehydrogenase (PGDH) mRNA expression in critical intrauterine tissues of pregnant baboons in late gestation and at spontaneous labor. In addition, we determined regulatory effects of betamethasone in vivo on chorionic and placental PGDH mRNA expression. PGDH mRNA was present in chorion, decidua, lower uterine segment, fundal myometrium, and cervix in late gestation but undetectable in amnion. PGDH mRNA significantly decreased in decidua and cervix during late gestation and in chorion and fundus during spontaneous labor. PGDH mRNA in lower uterine segment, decidua, cervix, and placenta was unchanged during spontaneous labor from late gestation levels. Betamethasone had no effect on chorionic and placental PGDH mRNA expression. In summary, our data suggest that PGDH mRNA expression is tightly controlled in gestation- and tissue-specific manners. Decreased chorionic and fundal PGDH abundance during labor and decreased decidua and cervical PGDH mRNA in late gestation allow local uterine prostaglandin accumulation and assist prostaglandin transfer to myometrium. Local differences in PGDH function may regulate tissue- and region-specific requirements for prostaglandins to promote and complete labor.
chorion; cervix; myometrium; placenta; parturition
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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PROSTAGLANDINS PRODUCED WITHIN the intrauterine tissues are widely considered to play key uterotonic roles in stimulating myometrial contraction (18, 19). Prostaglandins synthesized at various sites in the myometrium, decidua, chorion, amnion, and placenta are all likely to be involved in a variety of uterotonic and vascular functions in late gestation and during labor. However, prostaglandin output and action in utero during pregnancy and at parturition are dependent on metabolism as well as synthesis. Therefore it is important to evaluate the relative contribution of individual intrauterine tissues to prostaglandin metabolism in addition to their synthetic roles in preparation for and completion of parturition.
NAD+-dependent 15-hydroxy prostaglandin dehydrogenase
(PGDH) is the enzyme that catalyzes the initial oxidative step in the metabolism of PGE2 and F2
to their
biologically inactive 15-keto metabolites (1, 7). This is
the initial step in inactivating primary prostaglandins. In human
pregnancy, the chorion and placenta are major sites of PGDH activity.
It has been proposed that chorionic PGDH forms an effective metabolic
barrier that minimizes the passage of unmetabolized bioactive
prostaglandins derived from amnion and chorion to the uterine wall,
especially the myometrium for most of pregnancy (5, 24).
Because PGDH mRNA and protein as well as activity (24) are
decreased in chorion of women in labor, it has been postulated that, at
parturition, the protective barrier formed by PGDH in chorion
diminishes. As a direct consequence, prostaglandins produced by amnion
and chorion can more easily reach the myometrium to stimulate
myometrial contraction (24).
Studies from many different laboratories have demonstrated that fetal membranes, in particular amnion, are a major source of prostaglandins during labor (22, 25, 26). Although amnion is distributed throughout the uterus and the amniotic hindbag is surrounded by a larger amount of amnion than the forebag, amniotic forebag prostaglandins are surprisingly five to ten times higher than hindbag prostaglandin concentrations (12, 23). Recently we demonstrated that there are dramatic increases of PGH2 synthase (PGHS2) mRNA near term and during labor in the lower uterine segment and cervix, but not fundus, in the pregnant baboon (28). We proposed that this increased lower uterine segment and cervical PGHS2 abundance will promote lower uterine segment elongation and cervical effacement, essential prerequisite preparation before the onset of labor in the final weeks of gestation. We also proposed that increased prostaglandins in the amniotic forebag are the reflection of locally produced prostaglandins.
However, no data exist on PGDH expression in myometrium and cervix in late gestation and during human labor or in intrauterine tissues in nonhuman primate pregnancy. No single study has analyzed indexes of changes in prostaglandin metabolizing capability in each intrauterine tissue in the same subjects in precise relation to clear indexes of myometrial activity in primate pregnancy. Such a study is fundamental to determination of both the intrauterine site of origin and the output of increased prostaglandin production associated with normal term pregnancy and parturition. The pregnant baboon allows for the study of these various functions in normal primate intrauterine tissues in a manner not possible in normal human pregnancy. The current study was designed to characterize PGDH mRNA abundance in different intrauterine tissues and different regions of myometrium in baboon late gestation and labor. Glucocorticoids inhibit chorionic and placental PGDH mRNA expression in tissues removed at late gestation from animals not in labor and also tissues removed during labor cultured for 3 days in vitro (4, 20, 21). In the present study, we therefore examined the effect of maternal administration of betamethasone in vivo on the expression of chorionic and placental PGDH mRNA.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Pregnant baboons from the Southwest Foundation for Biomedical Research (San Antonio, TX) were harem mated, and gestational age was confirmed by ultrasonography. Fundal and lower uterine segment myometrium were obtained at cesarean hysterectomy under halothane general anesthesia performed in nine baboons not in labor at 121, 146, 153, 157, 162, 162, 177, 177, and 180 days gestation [term 175-185 days gestational age (GA)]. Cervix was collected from eight of these nine baboons, and decidua was collected from seven of the nine baboons. Uterine electromyographic (EMG) leads had been previously sited in the baboons from which tissues were obtained at 177, 177, and 180 days GA, because it was particularly important to obtain myometrial activity recordings to ascertain that these animals were not in labor. Animal care and electromyogram analysis are described elsewhere (15). Myometrial activity was monitored continuously and evaluated as being in the low-amplitude, infrequent contracture mode in all baboons not in labor. The cervix was uneffaced and closed in all of these animals. EMG analysis preceding cesarean hysterectomy revealed no myometrial contraction activity. Chorion was obtained at cesarean section from an additional nine pregnant baboons not in labor at 139, 139, 141, 157, 157, 167, 168, 177, and 177 days GA. Placenta was obtained at the following gestations from baboons not in labor: 121, 139, 141, 141, 141, 157, 162, 162, 177, and 177. Placenta and chorion were obtained from five pregnant baboons after maternal administration of four doses of 87.5 µg/kg betamethasone at 12-h intervals beginning at 124, 127, 129, 131, and 137 days GA. In all of these animals, myometrial activity was only of the contracture type. Cesarean hysterectomy was also performed on five animals in spontaneous labor. Four of these animals had myometrial EMG leads placed in the uterus. The gestational ages at hysterectomy were 164, 184, 191, and 193 days GA. Cervical dilation for these animals was 6, 3, 3, and 2 cm, respectively. In a fifth animal without EMG electrodes, cesarean hysterectomy was performed at 172 days GA with the cervix 4-cm dilated and fully effaced. Procedures were approved by the Cornell University Institutional Animal Care and Use Committee. Facilities were approved by the American Association for the Accreditation of Laboratory Animal Care.Samples of amnion, chorion, placenta, cervix and lower uterine segment, and fundal myometrium were dissected immediately and flash frozen for later total RNA or mRNA extraction. The lower uterine segment was defined as the portion of uterus superior to the internal cervical os and below a line 1 cm superior to the internal cervical os. The fundus was defined as the uterine portion immediately superior to the uterine cavity upper limit.
RT-PCR of PGDH cDNA in the Pregnant Baboon Chorion and Amnion
RT-PCR as described previously was performed (29). PCR was conducted at 35 cycles at the following conditions: 94°C for 1 min, 66°C for 1 min, 72°C for 1 min using the specific human PGDH primers. PGDH forward primer 5'-CATGCACGTGAACGGCAAAGTGG-3' and PGDH reverse primer 5'-CCATTGGCAATCAATGGTGGGTCC-3' were used to amplify a 683-bp fragment of the PGDH cDNA corresponding to nucleotides 17-700 in the human PGDH cDNA (6, GenBank Accession number: NM_000860). The specificity of PCR products were further confirmed by sequence analysis for their identity (GenBank Accession number pending). RT-PCR was also used to detect amnion PGDH mRNA.Subcloning and Sequencing of PGDH cDNA
PCR products amplified by PGDH specific primers were cloned directly into the pCR 2.1 vector using the TA-cloning kit (Invitrogen, San Diego, CA) and sequenced in an Applied Biosystems automated sequencer (ABI 377 DNA sequencer) at the core sequencing facility of Cornell University. The cloned fragments of PGDH were sequenced from at least two different clones and from both the coding and noncoding strands. The DNASTAR program (DNASTAR, Madison, WI) was used for alignments. The acquired sequence data were aligned against the GenBank databases at the National Center for Biotechnology Information (National Institutes of Health, Bethesda, MD) using BLAST to search for sequence matches.Northern Analysis
Polyadenylated RNA was extracted from frozen chorion, cervix, lower uterine segment, and fundal myometrium by oligo(dT) cellulose affinity chromatography using a commercial kit (Fast Track 2.0, Invitrogen, San Diego, CA). Total RNA was extracted from the placenta. Samples of polyadenylated RNA (2 µg/lane) or total RNA (30 µg/lane) were separated by electrophoresis on a 1.4% (wt/vol) agarose-0.66 M formaldehyde gel and transferred onto a nylon membrane (Gene Screen plus, DuPont-NEN) as described previously (30). Prehybridization (>1 h) and hybridization (>18 h) were carried out at 68°C. The probe concentration was ~1 × 106 counts · min
1 · ml1 of
hybridization buffer. Membranes were washed twice for 5 min in 2×
sodium chloride-sodium citrate (SSC) and 0.1% at 68°C temperature and twice for 15 min in 0.1× SSC and 0.1% SDS at 68°C. The same membranes were reprobed for 
-actin or 18S.
Synthesis of Probes
The cloned PGDH cDNAs in pCR II vector (Invitrogen), which include promoters for phage polymerases SP-6 to produce antisense probe and T-7 to produce sense probe, were linearized by an appropriate restriction enzyme, and antisense and sense riboprobes were synthesized using a commercial kit (MAXIscript, Ambion) labeled with [
-32P]UTP (800 Ci/mmol) (NEN Life Science). The
plasmid containing -actin cDNA with RNA polymerase promoters was
purchased from Ambion (catalog no. 7424).
Statistical Analysis
Comparison of two means was made using Student's t-test. Comparison of three or more means was made by analysis of variance, and multiple post hoc comparisons with Tukey's method were used for 95% confidence interval of pairwise differences. Statistical significance was set at the 5% level. Changes associated with gestation were analyzed by regression analysis. Data are presented throughout as means ± SE.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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PGDH cDNA Cloning From Pregnant Baboon Chorion
Our cloned baboon PGDH sequences (GenBank Accession number: AF229830) match coding region of human homolog cDNA and share 98% identity at the nucleotide level (683 nt for accession NM_000860 of human homologous cDNAs). RT-PCR could not detect PGDH mRNA in the amnion in 13 of 14 samples studied (data not shown). The small amount of PGDH mRNA in the one positive sample may represent contamination from the chorion.Northern Analysis
Tissue distribution.
PGDH mRNA was present in chorion (Fig.
1), decidua (Fig.
2), placenta (Fig.
3), fundus (Fig.
4), lower uterine segment (Fig. 4), and
cervix (Fig. 5). PGDH mRNA concentration
was significantly higher in cervix than the lower uterine segment in
late gestation (Fig. 6).
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Effect of gestation. PGDH mRNA significantly decreased in the decidua and cervix across the final third of gestation (Figs. 2 and 5). There were no gestational-associated changes of PGDH mRNA in chorion, fundus, and lower uterine segment.
Effect of labor. PGDH mRNA decreased during spontaneous labor in chorion (Fig. 1) and fundus (Fig. 4). PGDH mRNA did not change during spontaneous labor in lower uterine segment (Fig. 4), decidua (Fig. 2), cervix (Fig. 5), and placenta (Fig. 3). Because there was a GA decrease in cervix and decidua, values during labor were compared with the three samples obtained at the end of gestation.
Effect of betamethasone.
Maternal betamethasone administration did not alter chorionic and
placental PGDH mRNA expression. For this comparison, only the five
control animals of similar GA to the betamethasone-treated animals were
used (Fig. 7). No signals were present in
any tissues using the PGDH sense probe (data not shown).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study produced simultaneous data on PGDH mRNA abundance in individual uterine tissues from different functional regions of the uterus in the same subjects and with precise correlation with gestation- and labor-related myometrial activity patterns. Our aim was to provide a more complete picture of uterine and fetal prostaglandin metabolizing capability during the final stages of gestation and at spontaneous labor. PGDH mRNA was present in all intrauterine tissues and different regions of the uterus studied except amnion. In addition, we demonstrated tissue-specific decreases of PGDH mRNA during late gestation and spontaneous labor in the different tissues.
Our study is also the first to characterize myometrial PGDH mRNA expression in the different regions of the uterus that have distinct roles in the promotion and completion of labor: fundus, lower uterine segment, and cervix. The fundal and lower uterine segment myometrium contained similar concentrations of PGDH mRNA in contrast to the significantly higher PGDH mRNA in the cervix in late gestation; however, during labor, PGDH mRNA decreased only in the fundus. Lower uterine segment and cervical PGDH were unchanged during labor. Recently we found that there was no increase of PGHS2 mRNA in the fundus before labor or during labor. PGHS2 mRNA was higher in the lower uterine segment and cervix than the fundus and rose before labor in these tissues. PGHS2 mRNA remained elevated in the cervix and lower uterine segment during labor. These striking differences between the fundus and lower uterine segment and cervix suggest differential regulation as well as functions that are distinct to different stages of late gestation and labor. We proposed that the increased lower uterine segment and cervical PGHS2 abundance before labor serves to soften, elongate, and prepare these tissues for their unique dilatory role in parturition. It appears that these functions are achieved by increased synthesis rather than altered metabolism. In contrast, the important role of fundal contraction during the expulsive second stage of labor appears to be controlled more by decreased prostaglandin metabolism than increased synthesis.
Our observation that chorionic PGDH mRNA was high in late gestation, but significantly decreased during spontaneous labor, is similar to the results obtained in human pregnancy (20, 21). Several reports have indicated that the in vitro transfer of unmetabolized PGE2 across the full thickness of fetal membranes is low (14). Restricted transfer has been attributed to the high activity of chorionic PGDH as a protective barrier to prevent the passage of primary bioactive prostaglandins synthesized within the amnion or chorion from reaching the myometrium and stimulating the onset of labor (16). Therefore, any decrease in PGDH activity during labor could reduce the protective barrier formed by PGDH in chorion. As a result, prostaglandins produced in amnion and chorion could reach the myometrium more easily to stimulate uterine contraction. Such a decreased PGDH protective barrier may operate as another mechanism to enhance local myometrial prostaglandin accumulation to stimulate uterine contraction and other labor-related changes in function.
Fetal glucocorticoids are elevated in late gestation in human pregnancy
(7) and there is suggestive evidence for increased fetal
adrenal function in nonhuman primates (10, 13). In
addition, glucocorticoids are routinely administered to pregnant women
in premature labor (17). We therefore examined the effect
of in vivo glucocorticoid administration on chorionic and placental PGDH expression. We did not observe any effect of maternal
administration of betamethasone on chorionic or placental PGDH mRNA
expression at the dose used. Previous reports concerning the effects of
glucocorticoids on PGDH activity have been conflicting. Brennand and
co-workers (2), using explants of human amnion and chorion
disks obtained from membranes of patients at spontaneous labor and
elective cesarean section, reported that dexamethasone had no effect on
prostaglandin metabolism. Similarly, prostaglandin metabolism by
isolated cells from human chorion laeve obtained at term by
elective cesarean section was not affected by cortisol or dexamethasone
(8). In contrast, Patel and co-workers
(20) recently reported that cortisol demonstrated
a dose-dependent inhibitory effect on PGDH activity and levels of PGDH
mRNA in both placental and chorion trophoblast cells cultured in vitro
for 3 days. Responses were similar between tissues from laboring and
nonlaboring women (20). We cannot explain the discrepancy
in the findings of glucocorticoid's effect, or lack of it, on PGDH
expression in the different in vitro studies. It is likely that dose
and time from last exposure, tissue processing, and many other factors
affect results obtained in vitro. However, our study is the first to
examine glucocorticoid's effect in vivo on chorionic and placental
PGDH expression in primate pregnancy. The dose of betamethasone used in
the current study was calculated to reproduce the dose used in pregnant
women on a weight-adjusted basis. This dose did have a significant
effect in inducing baboon placental 11-hydroxysteroid dehydrogenase mRNA and protein expression (11). In addition,
betamethasone at the dose used induced both maternal and fetal
hypertension. The negative effect reported here should be interpreted
against these positive findings of this dosing regimen.
It is important to evaluate the changes in PGDH we have demonstrated in relation to the maternal endocrine changes that occur at the end of gestation. In both human and baboon pregnancy, maternal peripheral plasma progesterone concentration continues to rise up to the time of labor (3, 27). It has been proposed that local progesterone functions within fetal membranes may play a role in inhibiting PGDH expression associated with labor, because progesterone antagonists inhibited PGDH activity, whereas progesterone agonists stimulated PGDH activity on in vitro trophoblast cell culture (20). Estrogens did not alter placental or chorionic PGDH expression in vitro (20). Further studies are required to extend these observation in vitro to provide information on the effects of progesterone and estrogen on regulation of PGDH expression in vivo.
In addition to the integrated, new data on the regional distribution of PGDH mRNA, the key enzyme involved in the metabolism of prostaglandins in the late gestation and laboring primate uterus presented here, we also provided data for PGHS2 mRNA at the same period of gestation (28). Our data suggest that the expression of these two key enzymes is tightly controlled in enzyme-specific, GA-specific, tissue-specific, and uterine regional-specific manners. Dramatic increases in prostaglandin synthesizing capability preceding the onset of labor occur in the lower uterine segment and cervix (28). We hypothesize that these early changes in prostaglandin production in the lower uterine segment and cervix in the final weeks of gestation play a key and indispensable role in the normal initiation of parturition. In contrast, prostaglandin producing capability in uterine fundus remained low throughout the late gestation (28). To add to this picture, in the present study we demonstrated that prostaglandin metabolizing capability in the uterine fundus decreased dramatically during labor. As a result, both locally produced prostaglandins within the fundal myometrium and prostaglandins transferred from other tissues such as the chorion will be more available to stimulate the processes required for the promotion and completion of parturition.
Perspectives
Regulation of prostaglandin function in various uterine and fetal tissues requires evaluation of synthesis, degradation, and receptor activity. The present study clearly demonstrates that the message for PGDH, the key step in the overall metabolism of PGF2 and
PGE2, is distributed in a tissue-, region-, gestation-, and
labor-specific fashion. The decrease in chorion and fundal PGDH
abundance during labor and decreased decidual and cervical PGDH mRNA in
late gestation will allow local uterine prostaglandin accumulation and
assist prostaglandin transfer to the myometrium. We recently showed
that there are also tissue-, region-, gestation-, and labor-specific
changes in PGHS2 message in late primate pregnancy using
the pregnant baboon model. The changes we described would correspond to
the different functions the tissues must perform; for example, the fall
in PGDH in the cervix before labor in late gestation will enhance local
prostaglandin concentration. The rise in local prostaglandins is
considered a major feature in cervical softening and effacement.
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ACKNOWLEDGEMENTS |
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This work was supported by National Institutes of Health Grant HD-21350.
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FOOTNOTES |
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Address for reprint requests and other correspondence: P. W. Nathanielsz, Laboratory for Pregnancy and Newborn Research, Dept. of Biomedical Sciences, College of Veterinary Medicine, Cornell Univ., Ithaca, NY 14853-6401 (E-mail: pwn1{at}cornell.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 24 January 2000; accepted in final form 5 May 2000.
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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) or LUS (
) during late gestation (n = 9). LUS PGDH mRNA did not change during SL (D). FUN PGDH
mRNA decreased significantly during SL (D,
* P < 0.01, n = 5). Data presented
as means ± SE.
