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Ovary |
a Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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cumulus cells, granulosa cells, ovary, oviduct, ovulation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PGE2, a dominant prostanoid in the ovary, reverses some of the inhibitory effects of NSAIDs or COX-2 gene deficiency. An LH surge leads to production of a large amount of PGE2 within follicles [11]. These results indicate that some of the steps of ovulation are mediated by PGE2. The actions of this prostanoid are mediated by PGE receptors comprising four subtypes: EP1, EP2, EP3, and EP4 [12]. These subtypes are encoded by different genes and differ in their signal transduction pathways; the EP1 subtype is coupled to Ca2+ mobilization, EP2 and EP4 to cAMP formation, and EP3 to inhibition of adenylate cyclase [13]. Although many investigators have indicated the importance of PGE2 in the ovulation and fertilization processes, little is known about which receptor mediates the reproductive effects of PGE2. We and other groups previously revealed that the EP2 receptor plays critical roles in these processes, especially in ovulation and fertilization, in EP2 -/- mice [14–17]. Furthermore, we found that EP2 mRNA is induced in cumulus cells by a gonadotropin surge and that EP2 -/- mice have a severe deficiency in cumulus expansion, which is required for successful fertilization. These findings and similar defects found in COX-2 -/- mice have clearly highlighted the importance of PGE2 in ovulation and fertilization. However, no clear consensus has been established regarding localization and expression regulation of the PGE receptors in the ovarian follicles and oviducts during ovulation.
In this study, we focused on analysis of the temporal and regional expression patterns of mRNAs for EP4, EP2, and the COX isozymes in periovulatory follicles and oviducts of gonadotropin-treated mice during the ovulation period.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All experiments were conducted in accordance with the ethical standards established by the institutional animal care and use committee of Kyoto University. C57BL/6 mice were purchased from Japan SLC (Hamamatsu, Japan). Four-week-old female mice were housed under a 12L:12D cycle, with lights-on at 0800 h.
Superovulation
Five-week-old virgin mice, which were used as prepubertal animals, received a single i.p. injection of 5 IU eCG. After 48 h, mice were given an i.p. injection of 5 IU hCG. Mice were killed at different intervals after eCG or hCG treatment, and the ovaries and oviducts were isolated. Four ovaries from four mice were pooled for each time point and frozen in liquid nitrogen before RNA extraction. For in situ detection of mRNA expression, the ovary and oviduct were isolated and frozen in 2-isopentane at -50°C for preparation of sections and stored at -80°C until use. Cumulus-oocyte complexes (COCs) were isolated 48 h after eCG treatment or 3 and 9 h after hCG treatment by needling the ovaries in a 35-mm Petri dish containing saline with 0.3% BSA. Fourteen to 16 COCs were isolated from each of four animals for each time point. The COCs were pooled per animal, and RNA was extracted separately for each animal.
Reverse Transcription Polymerase Chain Reaction Analysis
Ovarian total RNA was isolated by the acid guanidinium thiocyanate-phenol-chloroform method [18], and total RNA from COCs was isolated by using the RNeasy Mini Kit (Qiagen Ltd., Valencia, CA). Complementary DNA was synthesized from ovarian total RNA (10 µg) and COC total RNA by using Moloney murine leukemia virus reverse transcriptase and the Superscript first-strand synthesis system (Invitrogen, Carlsbad, CA), respectively. Polymerase chain reaction (PCR) was performed using a GeneAmp PCR system 9700 (Perkin Elmer Applied Biosystems, Foster City, CA). Primers used in the PCR for EP1, EP2, EP3, EP4, COX-1, COX-2, and glyceraldehyde phosphate dehydrogenase (GAPDH) genes were as follows: EP1, 5'-ACC CTG CAT CCT GAG CAG CAC TGG CCC TCT-3' (sense primer) and 5'-CGA TGG CCA ACA CCA CCA ACA CCA GCA GGG-3' (antisense); EP2, 5'-TTC ATA TTC AAG AAA CCA GAC CCT GGT GGC-3' (sense) and 5'-AGG GAA GAG GTT TCA TCC ATG TAG GCA TTG-3' (antisense); EP3, 5'-ATC CTC GTG TAC CTG TCA CAG CGA CGC TGG-3' (sense) and 5'-TGC TCA ACC GAC ATC TGA TTG AAG ATC ATT-3' (antisense); EP4, 5'-GAC TGG ACC ACC AAC GTA ACG GCC TAC GCC-3' (sense) and 5'-ATG TCC TCC GAC TCT CTG AGC AGT GCT GGG-3' (antisense); COX-1, 5'-TGC ATG TGG CTG TGG ATG TCA TCAA-3' (sense) and 5'-CAC TAA GAC AGA CCC GTC ATC TCC A-3' (antisense); COX-2, 5'-GAG TGG GGT GAT GAG CAA CTA TTC C-3' (sense) and 5'-CTG TAG GGT TAA TGT CAT CTA GTC T-3' (antisense); GAPDH, 5'-TGA AGG TCG GTG TGA ACG GAT TTG GC-3' (sense) and 5'-CAT GTA GGC CAT GAG GTC CAC CAC-3' (antisense). The reaction conditions for the PCRs were as follows: for EP2, EP3, EP4, COX-1, and COX-2, denaturation at 94°C for 48 sec, annealing at 60°C for 42 sec, and extension at 72°C for 90 sec; for EP1, denaturation at 94°C for 48 sec, annealing at 68°C for 42 sec, and extension at 72°C for 90 sec; for GAPDH, denaturation at 94°C for 48 sec, annealing at 70°C for 48 sec, and extension at 72°C for 60 sec. The numbers of PCR cycles for ovarian RNA were 30, 28, 30, 30, and 25 for EP2, EP4, COX-1, COX-2, and GAPDH, respectively. The cycle numbers for PCR analysis of COC total RNA were 33, 31, 30, 25 and 24 for EP2, EP4, COX-1, COX-2, and GAPDH, respectively. All PCRs were confirmed to be in the logarithmic phase by monitoring the products obtained at the indicated number ±2 cycles. PCR products were electrophoresed on a 1.5% agarose gel and stained with ethidium bromide. The reverse transcription PCR (RT-PCR) experiments were independently repeated three times from the same total RNA material.
In Situ Hybridization
Ovarian and oviductal sections (10-µm thickness) were cut on a Jung Frigocut 3000E cryostat (Leica Instruments, Nussloch, Germany) and thaw-mounted onto poly-L-lysine-coated glass slides. The sections were fixed in 4% formalin in PBS for 10 min, rinsed in PBS, and acetylated with 0.25% acetic anhydride in 0.1 M triethanolamine-0.9% NaCl for 10 min at room temperature. After dehydration sequentially in 70%, 95%, and 100% ethanol, the sections were air dried and stored at -80°C until use. Mouse cDNAs for EP2, EP4, COX-1, and COX-2 were subcloned into pBluescript II (Stratagene, La Jolla, CA) for synthesis of antisense and sense complementary RNA probes [19, 20]. Riboprobes were synthesized by transcription with T3 or T7 RNA polymerase (Stratagene) in the presence of [
-35S]CTP. Cold antisense riboprobes were also synthesized by the same procedure using unlabeled nucleotides. Hybridization was carried out as described previously [19]. The specificity of the signal with each antisense probe was verified both by its disappearance with the addition of an excess of unlabeled probe and by the absence of specific hybridization with the sense probe (data not shown). Hybridization sections were dipped in nuclear track emulsion (NTB3; Eastern Kodak Co., Rochester, NY). After exposure for 5 wk at 4°C, the dipped slides for all probes were developed, fixed, and counterstained with hematoxylin and eosin. Six sections were examined for the expression of each mRNA at each time point in each ovary and oviduct, and four ovaries and oviducts were examined per time. The in situ hybridization experiments were repeated independently three times, and similar results were obtained (data not shown). All data used in the figures and for quantification were from experiments with the same labeled probes.
Quantification of In Situ Signals and Statistical Analysis
The ratio of hybridization signal-positive area:total cell area (positive area ratio) was quantified using the Image-Pro Plus software (Media Cybernetics, Silver Spring, MD). Within a marked area, the image analysis system determined the number of graphic pixels occupied by the silver grains (signal area) in the dark-field view. The program also counted the number of pixels occupied by the hematoxylin and eosin-stained area (cell area) within the marked area. Positive area ratio was then defined as the number of pixels of signal area per pixels of cell area. Six to eight follicles from each of four ovaries were examined at each time point. All data were reported as the mean ± SEM and were analyzed with a two-way ANOVA (time and cell type) and the Bonferroni multiple comparison method as post hoc tests. A P value of <0.05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Using RT-PCR analysis, we first investigated the expression of mRNAs for the PGE receptors EP1, EP2, EP3, and EP4 and for the COX isozymes in the ovaries of prepubertal mice treated with eCG and hCG. EP2 mRNA was consistently detected in the ovaries of mice treated or not treated with gonadotropins (Fig. 1). However, EP4 mRNA was detected in nontreated immature ovaries (P0), and the amount gradually decreased after eCG treatment. At 3 h after hCG treatment (H3) the EP4 mRNA level was temporarily increased but was decreased again at 6 h (H6) and then increased again at 9 h (H9). For COX-2 mRNA, a rapid increase was observed at H3 in the mouse ovaries. This high expression level was decreased at H6 and then increased again at H9. Although COX-1 mRNA was expressed during all the time points examined, increased expression was obtained in ovaries from H9 to H18. Neither EP1 nor EP3 mRNA expression was detectable in ovaries from any time points (data not shown).
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Because the expression levels of mRNAs for EP2, EP4,Expression of mRNAs for EP2, EP4, COX-1, and COX-2 in COCs isolated 48 h after eCG treatment or 3 and 9 h after hCG treatment by needling the ovaries in a 35-mm Petri dish containing saline with 0.3% BSA. Fourteen to 16 COCs were isolated from each of four animals for each time point. The COCs were pooled per animal, and RNA was extracted separately for each animal. PCR conditions were the same as those in . The cycle numbers for PCR analysis were 33, 31, 30, 25, and 24 for EP2, EP4, COX-1, COX-2, and GAPDH, respectively. All PCRs were confirmed to be in the logarithmic phase by monitoring the products obtained at the indicated number ± two cycles. The numbers on the top (1–6) represent COC total RNA isolated from different animals. Six animals per time point were analyzed, and similar results were obtained. > and the COX isozymes varied in a time-dependent manner in mouse ovaries after hCG treatment, the regional and cellular distribution of these mRNAs were determined by in situ hybridization analysis.
Cellular Localization of EP2, EP4, COX-1, and COX-2 mRNAs in Immature Ovaries
To investigate the cellular distribution of signals for EP2, EP4, COX-1, and COX-2 mRNA in immature ovarian tissue, in situ hybridization analysis was performed with immature ovaries from mice before injection of eCG. The signals for EP4 mRNA were localized mainly in oocytes of small preantral follicles (Fig. 2C), whereas the signals for EP2 mRNA were in the theca and interstitial area (Fig. 2B). Although faint signals for COX-1 mRNA appeared to be present in the interstitial cells, the cell population could not be identified because of the existence of a variety of cell types (data not shown). No significant signals for COX-2 mRNA were observed in the immature ovaries of mice (data not shown).
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Cellular Localization of EP2, EP4, COX-1, and COX-2 mRNAs in Preovulatory Follicles
Human chorionic gonadotropin causes a variety of responses, such as cumulus expansion in the COCs and proteolysis in the follicular wall, that are required for successful ovulation. Histological sections of the mouse ovary were processed for in situ detection of mRNAs for EP2, EP4, COX-1, and COX-2 at the following time points: 48 h after eCG injection (P48); 3 h after hCG injection (H3), the period corresponding to significant induction of COX-2 mRNA by gonadotropin (Fig. 1); and 9 h after hCG injection (H9), the period corresponding to just before the time of ovulation. In the ovary at P48, the signals for EP4, COX-1, and COX-2 mRNAs were undetectable, and only faint signals for EP2 mRNA were observed in the theca and interstitial area as observed in immature ovaries (data not shown). In contrast, at H3 the signals for EP2 and EP4 mRNAs were detected mainly in both granulosa and cumulus cells (Fig. 3, B and C). In addition, faint but consistent signals for EP2 mRNA were still observed in theca cells and interstitial cells. In contrast to strong signals for COX-2 mRNA, COX-1 mRNA signals were not detected in these cell types (Fig. 3, D and E). In the H9 ovaries, the signals for EP2 mRNA were mainly localized to cumulus cells (Fig. 3G), and the signals for EP4 mRNA were localized to granulosa cells (Fig. 3H). At this time point, signals for COX-1 mRNA were seen in granulosa cells (Fig. 3I). Strong signals for COX-2 mRNA were detected at both H3 and H9 in the granulosa and cumulus cells (Fig. 3, E and J).
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To quantitatively analyze the signals for EP2, EP4, COX-1, and COX-2 mRNAs in granulosa cells and cumulus cells at H3 and H9, the values of the positive area ratios were analyzed according to the procedures described in Materials and Methods. Each value of the positive area ratio for H3 or H9 was compared with that of P48 (Fig. 4). In H3 ovaries, the values for EP2, EP4, and COX-2 mRNAs were significantly elevated compared with values at P48 in both granulosa cells and cumulus cells. In the H9 ovaries compared with the H3 ovaries, the values for EP2 and COX-2 mRNAs were notably decreased in the granulosa cells but were maintained at high levels in cumulus cells. At this time, the values for EP2 and COX-2 mRNAs in cumulus cells were significantly higher than those in granulosa cells. In the H9 ovaries, the values for EP4 mRNA in both cell types were slightly decreased compared with those of H3 ovaries. In contrast, the value for COX-1 mRNA was significantly increased in the granulosa cells of H9 ovaries.
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In situ hybridization revealed that the intensities of the signals for EP2 and EP4 mRNAs in H3 follicles were stronger than those in H9 follicles (Fig. 3, B vs. G, C vs. H), although the intensities of the PCR bands were not so different from each other (Fig. 1). To assess this inconsistency, we performed RT-PCR analysis using COCs corresponding to P48, H3, and H9 as starting material. None of the mRNAs for EP2, EP4, COX-1, or COX-2 could be detected at P48 under these PCR conditions (Fig. 5). With hCG treatment, the levels of both EP4 mRNA and EP2 mRNA expression were clearly increased in COCs in the H3 follicles. Thereafter, the expression of EP2 mRNA was further stimulated and that of the EP4 mRNA was diminished in COCs in H9 follicles. However, COX-2 signals were rapidly increased by hCG treatment in H3 follicles, and COX-1 signals gradually increased as seen in H9 follicles.
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Cellular Localization of COX-1 and COX-2 mRNAs in Granulosa Cells of Follicles Just after Ovulation
At H9, in situ hybridization analysis revealed that the mRNA signals for the COX isozymes were expressed in granulosa cells of preovulatory follicles (Fig. 3, I and J). In the granulosa cells of H9 follicles, EP4 mRNA signals were apparent but those of EP2 mRNA were faint (Fig. 3, G and H). At 12 h after hCG injection, granulosa cells in the follicles start to differentiate into luteal cells. Therefore, expression of mRNAs for the COX isozymes and EP4 was examined in these cells. Messenger RNAs for COX-1 and COX-2 were still expressed in the granulosa cells of the ovulated follicles, as indicated by in situ hybridization analysis (Fig. 6). However, EP4 mRNA signals were not observed in these cells (data not shown).
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Cellular Localization of EP2, EP4, and COX-1 mRNAs in the Oviduct
The oviduct is a tube extending from the periovarial space to the uterine horns. Ovulated COCs enter the oviduct and stay in the ampulla, where the fertilization processes occur. Cumulus cells in follicles strongly express both EP2 and COX-2 mRNA (Fig. 3, B and E). Such expression of EP2 and COX-2 mRNA in cumulus cells was still found in the ovulated COCs within the ampulla of the oviduct (data not shown). In the oviducts, the signals for EP2 mRNA were mainly localized to the smooth muscle layer (Fig. 7B), especially to the highly ciliated area of the tract near the ovary. The signals for EP4 mRNA were observed in the epithelium throughout the oviduct (Fig. 7D). The distribution of the signals for COX-1 mRNA corresponded roughly to that for EP4 mRNA (Fig. 7C). No significant signals for COX-2 mRNA were observed throughout the oviduct (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The expression of the two COX isozymes and the two Gs-coupled EP receptors increased in particular follicle cells in response to gonadotropins. Expression of COX-2, EP2, and EP4 rapidly increased in both cumulus and granulosa cells 3 h after hCG injection, but cumulus cells dominantly expressed COX-2 and EP2 9 h after hCG treatment. COX-1 mRNA expression in granulosa cells was apparent only at 9 h after hCG administration. There is no doubt that the LH surge is a primary event leading to the induction of EP receptors and COX isozymes in preovulatory follicles, but the expression pattern is different for each between 3 h and 9 h. Because gonadotropins are known to stimulate the synthesis of various kinds of intrafollicular mediators [21], late induction or changes in expression may be mediated by other factors including PGs. In several cell types, COX-2-derived PGs stimulate COX-2 expression itself in an autocrine manner [22]. This positive feedback regulation by PGs may be a mechanism underlying distinct expression patterns between 3 h and 9 h.
Expression of EP4 and EP2 increased in both cumulus and granulosa cells as a gonadotropin-elicited rapid response (3 h). Although EP2-deficient mice but not EP4-deficient mice show a significant defect in the ovulation process [23], simultaneous induction of the two Gs-coupled PGE receptors suggested pivotal roles for PGE2 in the ovulation process; EP2 and EP4 might cooperatively work as a compensatory system for successful ovulation. Follicular rupture involves a complex series of biochemical and biophysical changes in the theca cells, cumulus cells, and granulosa cells, which interact with each other [21]. Gonadotropin-elicited interstitial collagenase (matrix metalloprotease 1) induction in granulosa cells, which is regarded as a key step in follicular rupture, was suppressed by treatment with indomethacin [21, 24, 25]. Miyaura et al. [26] recently demonstrated that EP4 is responsible for the PGE2-induced activation of matrix metalloproteases in mouse calvarian cells. EP2 and EP4 expressed in granulosa cells may play roles in ovulation in a similar fashion. Further analyses using EP-specific antagonists or EP2/EP4 double knockout mice are needed to evaluate the exact roles of PGE2 through each receptor subtype.
The present study also highlights COX-1 expression in granulosa cells as a late response (9 h after ovulation). Although the induction of COX-2 gene expression has been identifed in the ovaries of various animals around the ovulation period [5–8, 27, 28], very few researchers have analyzed COX-1 expression during ovulation except for one study of whole rat ovaries [29]. The function of COX-1 mRNA expression just before ovulation is currently unknown. RT-PCR analysis (Fig. 1) indicated that COX-2 mRNA expression also showed an early (3 h) and a late (9 h) increase after hCG injection, which coincides with the observations previously reported by Joyce et al. [28]. These results suggest that granulosa cells start to express both COX isozymes just before ovulation. Moreover, expression of COX-1 and COX-2 was detected in granulosa cells (corresponding to the cells differentiating into luteal cells) in follicles after ovulation (Fig. 6). Prostanoids synthesized by each enzyme may participate cooperatively in the final steps of the ovulation and/or postovulation processes.
We quantified the results in in situ hybridization by evaluating hybridization signal-positive area per total cell area to determine what percentage of the total cumulus or granulosa cells express a particular mRNA. This quantification analysis revealed that the value of the EP2-positive cells per total cumulus cells was higher in H9 ovaries than in H3 ovaries (see Fig. 4, Cumulus in panel EP2), even though the signal density for EP2 mRNA in the cumulus cells looked higher at H3 than at H9 (Fig. 3, B and G). The cumulus cells in H9 ovaries are less dense than those in H3 ovaries because of the cumulus expansion. Therefore, the sparse signals for EP2 mRNA in the cumulus cells of H9 ovaries reflect the lower cell density on this section apart from the ratio of EP2-positive cells to negative cells.
Expression of mRNAs for EP4 and EP2 in the Oviduct
Pharmacological experiments have demonstrated that exogenous PGE2 is able to inhibit contractions of the oviductal tube in the rabbit [30] and to decrease passage pressure in the rat oviduct [31]. In the present study, we clearly demonstrated that EP2 mRNA is expressed in the muscle layer. These results suggest that PGE2, via EP2, may contribute to relaxation of the oviduct, which is favorable for successful fertilization [32]. A severe defect in fertilization in EP2-deficient female mice may be partly due to a lack of effect of PGE2 in the oviduct. However, oviductal epithelia secrete glycoproteins and produce a flow in oviductal fluid by ciliary action [33]. In the rabbit oviduct, PGE2 stimulates ciliary activity in the epithelium [34]. PGE2 also stimulates mucin exocytosis from intestinal epithelial cells via EP4 [35]. Thus, EP4 may regulate both the secretion of glycoproteins and ciliary activity in the oviductal epithelium. Such mechanisms may act favorably in the process of fertilization.
Expression of EP4 and EP2 mRNAs in Preantral Follicles
EP4 mRNA expression was found in oocytes within preantral follicles. Because transcripts in oocytes are sometimes translationally dormant and are activated in a time-dependent manner [36], it is not clear whether the EP4 receptor proteins are expressed in the oocytes at this stage. There is little information on the effects of prostanoids on oocyte function, and the role of EP4 in oocytes remains to be clarified. However, we detected faint but significant signals for COX-1 mRNA in the interstitial area (Fig. 1). Therefore, very low levels of PGE2 may be constitutively synthesized by COX-1 and may act on EP4 in the oocytes at this stage.
EP4 mRNA is present in the cumulus and granulosa cells in the preovulatory follicles. COX-1 mRNA is expressed in the granulosa cells just before ovulation, in contrast to the preferred expression of EP2 and COX-2 mRNA in the cumulus cells. These results extend our knowledge of the expression of COX enzymes and PGE receptors and the possible active sites of PGE2 in the female reproductive processes.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence. FAX: 81 75 753 4557; e-mail: aichikaw{at}pharm.kyoto-u.ac.jp
Received: 14 January 2002.
First decision: 6 February 2002.
Accepted: 14 September 2002.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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