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Department of Molecular and Integrative Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City, Kansas 66160-7336
Address all correspondence and requests for reprints to: Dr. S. K. Dey, Department of Molecular and Integrative Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City, Kansas 66160-7338. E-mail: sdey{at}kumc.edu
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Introduction |
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The vasoactive, mitogenic, and/or differentiating properties of PGs (4)
place these lipid molecules as potential mediators of increased
endometrial capillary permeability, epithelial cell differentiation,
and stromal cell proliferation/differentiation to decidualization
during early events of implantation (5, 6). PGs are derived from
arachidonic acid by the cyclooxygenases (COX) pathway. COX, which
exists in two isoforms, COX-1 and COX-2, is the rate-limiting enzyme in
the biosynthetic pathway that converts arachidonic acid into
PGH2. PGH2 is then converted by specific PG
synthases into diverse PG isoforms, including PGE2,
PGF2
, PGD2, and PGI2 (4). These
PGs exert diverse effects through their G protein-coupled cell surface
receptors (7). Among the PGs, PGE2 mediates many biological
functions in cardiovascular, pulmonary, renal, endocrine,
gastrointestinal, neural, reproductive, and immune systems (8).
PGE2 can bind to and activate a set of functionally
distinct cell surface receptors, EP1, EP2,
EP3, and EP4, which are classified on the basis
of their responses to various agonists and antagonists to
PGE2. They also exhibit different characteristics with
respect to their structures, tissue distribution, and signal
transduction mechanisms (7). Thus, EP1 is coupled to
Ca2+ mobilization, whereas both EP2 and
EP4 subtypes are coupled to the stimulation of adenylyl
cyclase via Gs. In contrast, EP3 is coupled to
Gi, which inhibits adenylyl cyclase activity. Cell surface
receptors for PGF2, PGD2, PGI2,
or thromboxane have also been identified as FP, DP, IP, and TP,
respectively (9, 10, 11, 12).
Previously, we demonstrated that EP1, EP3, EP4, and FP genes are expressed in the mouse uterus during the periimplantation period in a spatio-temporal manner (13). The expression of EP3 and FP in the circular muscle of the myometrium on days 3–5 suggested that this muscle layer is the target for PG-mediated uterine contractions required for embryo transport and spacing. In contrast, the expression of EP3 in a subpopulation of stromal cells at the mesometrial pole and of EP4 in the epithelium and stroma on these days suggested that the activation of these receptor subtypes by PGE2 could be important for preparation of the uterus for implantation. Further, expression of EP1, EP3, and EP4 in site-specific decidual cells during the postimplantation period suggested PGE2’s role in various aspects of decidualization process. However, information regarding the expression of EP2, an important member of the PGE2 receptor subtypes, in the uterus is very limited, except for a report describing the expression of this messenger RNA (mRNA) in the mouse uterus during pseudopregnancy (14). However, data concerning whether the expression of this gene in the uterus is influenced by developing embryos, ovarian steroids, and/or decidualization are totally lacking. In the present investigation, we examined the temporal and cell-specific expression of the EP2 gene in the mouse uterus during the periimplantation period (days 1–8 of pregnancy) as well as its regulation during experimentally induced delayed implantation and after termination of the delayed implantation. We also examined the regulation of this gene in the ovariectomized adult uterus by estrogen and P4. The results establish that EP2 is associated with the luminal epithelial cell differentiation that is necessary for blastocyst implantation and that this gene is regulated synergistically by estrogen and P4, but not by developing and/or implanting embryo.
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Materials and Methods |
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To induce and maintain delayed implantation, mice were ovariectomized at 0800–0900 h on day 4 of pregnancy and received daily injections of P4 from days 5–7 (2 mg/mouse; Sigma Chemical Co., St. Louis, MO) (2, 15). To terminate delayed implantation and to induce blastocyst activation, the P4-primed delayed implanting mice were given an injection of 17ß-estradiol (E2; 25 ng/mice; Sigma) on the third day of the delay (day 7). Mice were killed 24 h after treatment with the respective steroid hormones, and their uteri were collected for in situ hybridization. The first visually detectable implantation sites after blue dye injection become evident 18–24 h after an E2 injection.
To determine the effects of estrogen and P4, mice were ovariectomized regardless of the stage of estrous cycle and rested for 2 weeks. They were treated with P4 (2 mg/mouse) for 2 days with or without an injection of E2 (100 ng/mouse) on the second day of P4 treatment. To neutralize the effects of P4 or E2, mice were injected with RU-486 (400 µg/mouse) or ICI-182780 (50 µg/mouse), respectively. Control animals received vehicle (0.1 ml oil/mouse) only. Mice were killed 24 h after the last injection, and their uteri were collected for in situ hybridization. All steroids and antagonists were dissolved in sesame oil and injected sc (0.1 ml/mouse).
Hybridization probes
A mouse-specific complementary DNA to EP2 was
generously provided by Dr. Ichikawa (Kyoto University, Kyoto, Japan)
(16). For Northern hybridization, antisense 32P-labeled
complementary RNA (cRNA) probe was generated, whereas for in
situ hybridization, sense or antisense 35S-labeled
cRNA probe was generated using appropriate polymerases. A part of the
ribosomal protein L7 (rpL7) complementary DNA was subcloned into
pCR-Script vector containing promoter for T7 polymerase and used as a
template for synthesis of 32P-labeled antisense rpL7 RNA
probe (17). The probes had specific activities of about 2 x
109 dpm/µg.
Northern blot hybridization
Total RNA was extracted from uteri by a modified guanidine
thiocyanate procedure (18, 19). Polyadenylated [poly(A)+]
RNA samples were isolated by oligo(deoxythymidine)-cellulose column
chromatography (20). Poly(A)+ RNA samples (2.0 µg) were
denatured, separated by formaldehyde-agarose gel electrophoresis,
transferred, and cross-linked to nylon membranes by UV irradiation.
Northern blots were prehybridized and hybridized as described
previously (21). Briefly, hybridization was carried out for 20 h
at 68 C in 3 x SET (1 x SET = 150 mM NaCl,
5 mM EDTA, and 10 mM Tris-HCl, pH 8.0), 20
mM phosphate buffer (pH 7.2), 250 µg/ml transfer RNA,
10% dextran sulfate, and approximately 2 x 106
counts/min of 32P-labeled antisense RNA probe/ml
hybridization buffer. After hybridization, the blots were washed once
in 1 x SSC (standard saline citrate)-0.1% SDS for 1 h at 68
C, followed by a second washing in 0.3 x SSC-0.1% SDS for 1
h under the same conditions, and the hybrids were detected by
autoradiography. Stripping of the hybridized probe before subsequent
rehybridization was achieved as described previously (21). Each blot
was first hybridized to the EP2 probe and then to the rpL7
probe (a housekeeping gene) to confirm integrity, equal loading, and
blotting of RNA samples. Northern blot hybridization experiments were
repeated three times using independent RNA samples.
In situ hybridization
In situ hybridization was performed as described
previously (17, 18). Frozen uterine sections (10 µm) were mounted
onto poly-L-lysine-coated slides and stored at -70 C until
used. When required, frozen sections were cut serially to detect the
sites of blastocysts. After removal from -70 C, the slides with the
uterine sections were placed on a slide warmer (37 C) for 1 min and
then fixed in 4% paraformaldehyde in PBS for 15 min at 4 C. After
prehybridization, uterine sections were hybridized to
35S-labeled antisense EP2 cRNA probe for 4
h at 45 C. As negative controls, uterine sections were hybridized with
the 35S-labeled sense probe. After hybridization and
washing, the slides were incubated with ribonuclease A (RNase A; 20
µg/ml) at 37 C for 20 min. RNase A-resistant hybrids were
detected within 3–5 days of autoradiography using Kodak NTB-2 liquid
emulsion. The slides were poststained with hematoxylin and eosin.
In situ hybridization experiments were repeated at least
twice, using independent samples.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). As
reported previously (16), two transcripts (2.2 and 2.8 kilobases) were
detected in poly(A)+-enriched whole uterine RNA samples.
EP2 mRNAs were primarily detected on days 4 and 5 of
pregnancy, preceded or followed by very low levels of expression on
other days of pregnancy.
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, A and B) and 2 (data not shown), no
specific signals for EP2 mRNA were detected in any uterine
cell type. In contrast, weak signals were first detected exclusively in
the luminal epithelium on day 3 (data not shown) followed by
augmentation of these signals on days 4 and 5 of pregnancy (Fig. 2, C–F). Furthermore, the signals were present throughout the luminal
epithelium regardless of the location of blastocysts. No accumulation,
however, was noted in the glandular epithelium. Autoradiographic
signals were also not observed in decidualizing stroma during the
postimplantation period (days 6–8); only the remaining luminal
epithelium exhibited signals for this mRNA during this period. The
photomicrographs for day 6 are shown (Fig. 2, G and H). The heightened
signals in the luminal epithelium on days 4 and 5 are consistent with
the results of Northern blot hybridization (Fig. 1
). No positive
autoradiographic signals were detected in sections hybridized with the
sense probe (data not shown).
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, compare A and B vs. C
and D). An interference with estrogen functions by ICI 182780, an ER
antagonist, on day 4 also inhibited implantation on day 5 and
down-regulated the luminal epithelial accumulation of this mRNA (Fig. 3, E and F). However, this down-regulation was modest than when
P4 effects were neutralized.
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).
Autoradiographic signals were detected along the entire uterine luminal
epithelium of P4-treated delayed implanting mice (Fig. 4, A
and B). Signals were greatly augmented when the implantation process
was resumed by an injection of E2 (Fig. 4, C and D).
However, this up-regulation was again noted regardless of the location
of the activated blastocysts. This suggested that luminal epithelial
expression of EP2 mRNA is regulated primarily by steroid
hormones, but not by resident blastocysts.
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, A–D) were used. Mice were killed 24 h after the last injection,
and in situ hybridization was performed on uterine sections.
Basal levels of EP2 mRNA accumulation were observed in the
luminal epithelium of ovariectomized mice treated with oil (vehicle)
only (Fig. 5A). Although a single injection of E2
down-regulated this basal level of expression, treating the mice with
P4 for 2 days up-regulated the level of this mRNA in the
luminal epithelium (Fig. 5, B and C). Furthermore, this
P4-up-regulated EP2 mRNA expression was
remarkably enhanced when E2 treatment was superimposed on
P4 priming (Fig. 5D). P4 induction of
EP2 mRNA was attenuated by prior treatment of mice with a
PR antagonist, RU-486 (Fig. 5E). In contrast, although treatment with
this P4 antagonist greatly reduced the levels of
EP2 mRNA in P4- plus E2-treated
uterus (Fig. 5F), treatment with a specific estrogen antagonist,
ICI-182780, maintained levels comparable to those observed in
P4-only-treated uterus (Fig. 5G). These results suggest
that P4 is the prime regulator of the EP2 gene
in the luminal epithelium, although a cooperative effect of
E2 is operative only when it is superimposed upon
P4 priming. The results obtained from normal pregnancy and
delayed implantation models support this unique pattern of steroidal
regulation of EP2 in the uterus.
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Discussion |
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Both PGE2 and cAMP are known to be involved in stromal cell proliferation and decidualization (5, 6, 25). As the deepitheliated uterus fails to undergo decidualization in response to experimental stimuli, a signal(s) emanating from the luminal epithelium has been considered important for the initiation of stromal cell decidualization (26). Thus, it is possible that elevated levels of cAMP resulting from the activation of epithelial EP2 by PGE2 may participate in transmission of the luminal epithelial cell signals to the stroma for decidualization. On the other hand, there is evidence that information emanating from the stroma also influences epithelial cell functions (27). Thus, a cross-talk between the luminal epithelium and stroma by the coordinated actions of epithelial EP2 and stromal EP4 (13), both of which are coupled to stimulation of adenylyl cyclase, could be important for the initiation of implantation and decidualization. The induction of implantation by intraluminal injection of (Bu)2cAMP in the P4-maintained delayed implanting mice in the absence of estrogen (28) or rapid increases in intracellular cAMP after induction of decidual cell reaction in the hormonally primed uterus (25) is supportive of this possibility.
Our study using the experimentally induced delayed implantation model demonstrates that uterine expression of EP2 is not influenced by either dormant or activated blastocysts; rather, this expression is regulated by ovarian steroids P4 and/or E2. The similar expression pattern of EP2 in the pseudopregnant mouse uterus (15) as that in the pregnant uterus on days 4 and 5 reinforces the fact that this gene in the mouse uterus is primarily regulated by steroid hormones. Our present investigation further demonstrates that the EP2 gene is regulated uniquely in the uterus by P4 and E2, in that P4 up-regulates its expression, and E2 further potentiates this P4 effects, although E2 alone down-regulates the expression. The effects of P4 and E2 could be either synergistic or antagonistic with respect to various uterine functions and gene expression in a temporal and cell-specific manner. For example, synergistic and antagonistic effects of P4 and E2 on epithelial and stromal cell proliferation and/or differentiation, and their antagonistic effects on epithelial Muc-1, lactoferrin, amphiregulin, and erbB2 genes are well documented (3, 17, 21, 29, 30). As both P4 and estrogen are essential for implantation in the mouse, synergistic as well as antagonistic effects of these steroids at the molecular and cellular levels appear to be essential for successful implantation. The up-regulation of EP2 in the luminal epithelium by P4 and E2 is the first example of true synergism between these two steroids at the molecular level in preparing the uterus for implantation. Synergistic modulation of the EP2 gene by P4 and E2 is consistent with its expression pattern in normal pregnant uterus on days 4 and 5 when the uterus has been exposed to rising P4 levels and preimplantation estrogen secretion. The effects of P4 and/or E2 on uterine EP2 expression is mediated by classical nuclear PR and ER, as PR and ER antagonists abrogated the effects of P4 and/or E2. Although synergistic and antagonistic cross-talk between ER and PR in gene expression has been studied (31, 32), better understanding of this cross-talk requires further investigation. In this respect, the EP2 should serve as a candidate gene to study synergism between steroid hormone receptors.
Our previous and present investigations point toward the importance of ligand receptor signaling with PGs in the process of implantation and decidualization, and these events are attributes of the compartmentalized generation of PGs and/or expression of their receptors in the uterus during the periimplantation period. Application of PGE2 receptor subtype-specific antagonists or targeting of these genes by homologous recombination will address their definitive roles in implantation and uterine biology.
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Acknowledgments |
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Footnotes |
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2 Kansas Health Foundation predoctoral fellow.
Received June 6, 1997.
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