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Biology of Reproduction 67, 1588-1592 (2002)
© 2002 Society for the Study of Reproduction, Inc.

Regular Article

Nitric Oxide Inhibits Oocyte Meiotic Maturation

Yasuhiko Nakamura1,a, Yoshiaki Yamagataa, Norihiro Suginoa, Hisako Takayamaa, and Hiroshi Katoa

a Reproductive, Pediatric, and Infectious Science, Yamaguchi University School of Medicine, Ube 755-8505, Japan


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Recently, we have found that the nitrate/nitrite concentrations in preovulatory follicles significantly decrease after hCG injection and that inducible nitric oxide synthase (iNOS) plays a main role in the decrease of the intrafollicular nitric oxide (NO) concentration. The purpose of the present study was to investigate the role of NO on oocyte meiotic maturation and to consider the physiological means of the decrease in intrafollicular NO concentration. Immature rats received 15 IU of eCG, and ovaries were removed under ether anesthesia 48 h later. Each ovary was bluntly divided into five or six pieces containing from four to seven preovulatory follicles under the microscope and then incubated with hCG, aminoguanidine (AG; an iNOS inhibitor), or S-nitroso-L-acetyl penicillamine (SNAP; an NO donor) for 5 h. After incubation, preovulatory follicles were punctured, and germinal vesicle breakdown (GVBD) was observed. Also, cGMP concentrations in these follicles were measured. Next, denuded oocytes were recovered from preovulatory follicles at 48 h after injection of 15 IU of eCG and incubated with SNAP with or without ferrous hemoglobin. Every 30 min up to 12 h, GVBD was observed. Both AG and hCG promoted GVBD, and SNAP prevented this effect. In addition, AG decreased intrafollicular cGMP levels, and the concomitant addition of SNAP prevented this decrease. Finally, SNAP dose-dependently inhibited GVBD in denuded oocyte, and this effect of SNAP was reversed by the addition of hemoglobin. We conclude that the iNOS-NO-(cGMP) axis may play an important role in oocyte meiotic maturation.

cyclic guanosine monophosphate, meiosis, nitric oxide, ovulation, ovum


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Nitric oxide (NO) is produced by three different NO synthase (NOS) isoforms: 1) neuronal NOS (nNOS), 2) endothelial NOS (eNOS), and 3) inducible NOS (iNOS). Of the three NOS isoenzymes, ovaries express eNOS and iNOS but not nNOS [1–4]. Expression of eNOS increases after LH surge or hCG injection [1–3], and eNOS-derived NO stimulates the ovulatory process [5–11]. The changes of iNOS expression during this process are controversial [1–4, 12], and the role of iNOS-derived NO is unclear. Recently, we have found that the nitrate/nitrite concentrations in preovulatory follicles significantly decrease after hCG injection [13]. In that study, eNOS expression was detected in the thecal layer and increased after hCG injection, but iNOS expression was mainly detected in granulosa cells and decreased after hCG injection, which indicated that the decrease of intrafollicular NO metabolites after hCG injection was likely caused by the decrease of iNOS expression in granulosa cells [13]. Why is intrafollicular NO concentration high before hCG injection and decreased after hCG injection?

A fully grown oocyte enclosed in a preovulatory follicle is arrested at prophase I of the first meiotic division [14]. To keep a high cAMP concentration in the oocyte is the key for this meiotic arrest [15]. Meiosis resumption is triggered by a midcycle LH surge, with a decrease of oocyte cAMP concentration [15, 16], and the oocytes induced to resume meiosis proceed to the first or second metaphase to be inseminated [14]. Because the oocyte extruded from the preovulatory follicle shows spontaneous progression of meiosis [17], inhibitory substances in the preovulatory follicle likely prevent oocyte meiotic maturation before the LH surge and lose their inhibitory effects after the surge [18]. Some candidates for these inhibitory substances have been reported, including oocyte maturation inhibitor [19], purine [20], steroids [21], and cGMP [15, 22, 23]. Elevated cGMP levels can inhibit spontaneous oocyte maturation [23] and also inhibit phosphodiesterase activity in the oocyte, elevating cAMP levels [24]. The levels of cGMP decrease in parallel to oocyte maturation in rats [23], but the mechanism controlling its production is unclear. Nitric oxide is a well-known factor that stimulates cGMP production [25]. Moreover, recent studies indicate that NO inhibits cell proliferation by affecting cell-cycle regulators of G1-S phase in smooth muscle cells [26–28] and of G2-M phase in smooth muscle cells [29] or macrophage-like cells [30].

In the present study, we examined the role of NO in oocyte meiotic maturation during eCG/hCG-induced ovulation in immature rats to reveal the means of the decrease of intrafollicular NO production by the iNOS-NO system after hCG.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals

Experimental protocols were approved by the Committee for Ethics on Animal Experimentation at Yamaguchi University School of Medicine, and all experiments were carried out under the control of the Guidelines for Animal Experimentation at Yamaguchi University School of Medicine in compliance with Japanese Law No. 105 and Notification No. 6.

Immature Sprague-Dawley rats (Japan SLC, Inc., Hamamatsu, Japan) were housed in a controlled room with a 14L:10D photoperiod and free access to standard rat chow and water. When they were 26 days old, all rats received an s.c. injection of 15 IU of eCG (Sigma, St. Louis, MO) in 0.15 ml of saline. All rats received laparotomy under deep ether anesthesia at 48 h after eCG injection, and the ovaries were quickly removed for the following experiments and the rats killed by exsanguination.

Culture of Divided Ovaries

Each ovary collected from four rats was bluntly divided into five or six pieces containing four to seven preovulatory follicles in PBS under a stereomicroscope. In the first experiment, to examine the effect of the iNOS-NO system on oocyte maturation, the divided ovarian pieces were placed in a 3.5-cm dish in 3 ml of Dulbecco modified Eagle medium (DMEM; Sigma) containing 10% (w/v) fetal calf serum (FCS) with various doses (0, 1, 10, or 100 mM) of aminoguanidine (AG; Sigma), an iNOS inhibitor. In the second experiment, S-nitroso-L-acetyl penicillamine (SNAP; 500 µM; Dojindo, Kumamoto, Japan), an NO donor, was added to the preovulatory follicles with 100 mM AG. In the third experiment, to examine the relation between hCG and NO during oocyte maturation, the ovarian pieces were placed in a 3.5-cm dish in 3 ml of DMEM containing 10% FCS and hCG (1 IU/ml) with or without SNAP (500 µM).

After a 5- or 10-h incubation at 37°C in a humidified 5% CO2 incubator, cumulus-oocyte complexes (COCs) were isolated from cultured ovaries and then exposed to 0.5% (w/v) hyaluronidase solution (Sigma) and repeated pipetting through a narrow-bore glass pipette. In the second and third experiments, only 5-h incubation studies were made. Denuded oocytes were collected, and germinal vesicle breakdown (GVBD) was observed under a stereomicroscope. Oocytes showing a germinal vesicle were considered to be still arrested in prophase I and those showing GVBD to have resumed meiosis [23]. Each group of each experiment consisted of 12 ± 4 (mean ± SD) oocytes, and the same experiments were repeated three times for 5-h incubation and twice for 10-h incubation studies.

In the second experiment, after 5-h incubation of each ovarian piece, preovulatory follicles were dissected from those ovarian pieces, and follicular fluid was collected by puncturing 10 follicles with a 27-gauge needle in a watch glass containing 200 µl of saline after 5-h incubation. The follicular fluid was centrifuged at 2000 x g for 15 min, and the supernatant was stored for cGMP assay. The cGMP analysis was performed with a cGMP EIA kit (Cayman, Ann Arbor, MI).

Denuded Oocyte Culture

At 48 h after eCG injection, COCs were removed from preovulatory follicles in three rats and treated in 0.5% hyaluronidase, and denuded oocytes were obtained from the COCs by mechanically removing cumulus cells with a narrow-bore glass pipette. Denuded oocytes were washed three times with fresh DMEM medium and incubated in 100 µl of DMEM containing 10% FCS with various concentrations (0, 10, 100, or 500 µM) of SNAP at 37°C in a humidified 5% CO2 incubator. In the next experiment, denuded oocytes were incubated in the presence of 500 µM SNAP with or without 20 µg/ml of ferrous hemoglobin (Hb; Sigma) under the same conditions. Every 30 min up to 12 h, GVBD was observed under a stereomicroscope. Each group of both experiments consisted of 15 ± 4 (mean ± SD) oocytes, and the same experiments were repeated three times.

Statistical Analysis

Data in the divided ovarian culture studies are presented as the mean ± SEM of three sets of experiments. Data were analyzed by one-way ANOVA and the Duncan new multiple range test. The results of denuded oocyte cultures are presented as mean values of all oocytes in each group. These results were evaluated by log-rank test. Differences were considered to be significant at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Effects of iNOS Inhibitor, hCG, and NO Donor on GVBD in Ovarian Culture

The percentage of oocytes at the germinal vesicle stage was significantly lower (P < 0.01) in the group receiving 10 and 100 mM AG than in the control group after 5 h of incubation (Fig. 1A). This GVBD-promoting effect of 100 mM AG was significantly reversed (P < 0.05) by the addition of 500 µM SNAP (Fig. 1B).



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  		FIG. 1. Effects of AG and SNAP on GVBD in preovulatory follicles. Percentages of oocytes at germinal vesicle stage after treatment with AG at various doses (A) and AG, AG with SNAP, or SNAP alone (B). Data represent the mean ± SEM of three separate experiments. aP < 0.01 vs. control, bP < 0.05 vs. AG-treatment group

After the 5-h incubation, the percentage of oocytes at the germinal vesicle stage was significantly lower (P < 0.05) in the hCG group than in the control group, and this effect was significantly reversed (P < 0.05) by the addition of 500 µM SNAP (Fig. 2).



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  		FIG. 2. Effects of hCG and SNAP on GVBD in preovulatory follicles. Percentages of oocytes at germinal vesicle stage after treatment with hCG, hCG with SNAP, or SNAP alone. Data represent the mean ± SEM of three separate experiments. aP < 0.05 vs. control, bP < 0.05 vs. hCG-treatment group

All oocytes showed GVBD in the group receiving 10 and 100 mM AG after 10 h of incubation (Table 1).


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  		TABLE 1. The percentage of oocytes at germinal vesicle stage after 10-h incubation with or without AG (1, 10, 100 mM).a

Effects of NO Donor on GVBD in Denuded Oocyte Culture

The time required for GVBD was dependent on the doses of SNAP and was significantly longer (P < 0.01) in the 500 µM SNAP group than in the control group (Fig. 3A). This inhibitory effect of SNAP on GVBD was significantly reversed (P < 0.01) by the addition of 20 µg/ml of Hb (Fig. 3B).



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  		FIG. 3. Time-course changes of GVBD of denuded oocytes. Each plot shows the changes in percentage of oocytes at germinal vesicle stage in the presence of various doses of SNAP (A) and SNAP with or without Hb (B). At least 38 (A) or 51 (B) oocytes were analyzed in each treatment, and plotted data are the means of all oocytes in each group

Effects of AG on Intrafollicular cGMP Levels

After the 5-h incubation, the intrafollicular cGMP concentration was significantly lower (P < 0.01) in the AG group than in the control group (Table 2). This lowered cGMP production was completely reversed by the addition of SNAP (Table 2).


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  		TABLE 2. Effects of AG with and without SNAP on cGMP concentrations in preovulatory follicles


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, hCG induced GVBD in oocytes of preovulatory follicles, and the NO donor prevented this phenomenon. Moreover, the inhibitor of iNOS (i.e., AG) induced GVBD as well as hCG, and the NO donor prevented this phenomenon. Recently, we have reported that NO metabolite (nitrate/nitrite) concentrations in preovulatory follicles are high before and decrease after hCG injection, and these changes likely reflect changes of iNOS, but not of eNOS, expression in granulosa cells of preovulatory follicles [13]. The AG selectively inhibits NO production by iNOS [31]. NG-monomethyl-L-arginine (L-NMMA) is equivalently potent to inhibit iNOS but is more potent for eNOS compared with AG [31], and L-NMMA induced GVBD to the same level as AG (unpublished data). Together with these findings, the present results suggest that iNOS-derived NO may be one of the oocyte maturation inhibitors. An intrafollicular high-concentration milieu of NO likely plays a role in the meiotic arrest of oocytes, and the decrease of NO concentration after hCG injection is an important event for oocyte maturation.

We hypothesize (Fig. 4) that the eNOS-NO system and iNOS-NO system may play a different role in the outside and inside of the basement membrane of the preovulatory follicle during ovulation. Expression of eNOS, mainly localized in the thecal layer, significantly increased after hCG injection [1–3, 13]. In addition, eNOS-derived NO in theca cell layers increases local blood flow in preovulatory follicles, which may result in permitting ovulation-inducing or oocyte-maturating factors to enter preovulatory follicles. Although oocyte meiotic maturation is reported to be inhibited in eNOS knock-out mice [10, 32], it is likely to be the results in the poor blood supply to those follicles before and during ovulation. Jablonka-Shariff et al. [33] also reported that the oocyte itself expressed eNOS and that the oral administration of NOS inhibitor blocked oocyte maturation. However, whether eNOS-derived NO from oocyte contributes to its own maturation directly is unclear, because no obvious change of eNOS expression is seen in the oocyte during the ovulatory process. On the contrary, iNOS expression, mainly localized in granulosa cells, significantly decreased after hCG injection, which induced a decrease of NO concentrations in preovulatory follicular fluid [13]. Higher concentration of NO inhibits progesterone production [13, 34] and induces apoptosis in rat granulosa cells [13]. Those harmful effects of NO are also reported during embryonic development in mice [35]. Therefore, the decrease of NO generation by iNOS at the inside of the basement membrane after hCG injection is physiologically reasonable and important. Moreover, the present results indicate that the decrease of iNOS-derived NO production may play an important role for oocyte meiotic maturation (i.e., GVBD).



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  		FIG. 4. A scheme showing the different roles of the iNOS-NO and eNOS-NO systems in preovulatory follicles before and after hCG injection. Injection of hCG increases eNOS expression in theca cell layer, and eNOS-derived NO increases blood supply to the preovulatory follicles. On the contrary, iNOS expression is decreased in granulosa cells, which induces the decrease of intrafollicular NO concentration; this change supports progesterone production in granulosa cells, saves granulosa cells from apoptosis, and helps oocyte meiotic maturation

The present study also revealed that the iNOS inhibitor decreased cGMP production in preovulatory follicles and that the addition of an NO donor blocked this suppression. These results indicate that iNOS-derived NO produces a high cGMP concentration in preovulatory follicles. Produced by the granulosa cells and transported via gap junctions into the oocyte, cGMP has an important role in maintaining the meiotic arrest of oocytes [15]. Törnell et al. [15, 23] reported that the level of both cGMP and cAMP decreased in oocytes parallel to spontaneous meiosis and that the microinjection of these substances into oocytes caused a delay in oocyte maturation. In fact, cGMP maintains the meiotic arrest of preovulatory oocytes via two pathways: one involving sustenance in cAMP level by inhibition of oocyte cAMP phosphodiesterase and the other involving activation of cGMP-dependent protein kinase in oocytes [15]. Mitogen-activated protein kinase (MAPK) may play an important role in initiating mammalian oocyte maturation [14, 36]. Interestingly, NO inhibits MAPK activity via generation of cGMP [37]. These previous results combined with our present results indicate that iNOS-derived NO maintains the intrafollicular cGMP level to inhibit oocyte meiotic maturation.

In the present study, we also found that NO inhibited directly oocyte maturation in denuded oocyte cultures. A recent study showed that NO directly inhibits MAPK via activation of tyrosine kinase [38]. In the rat, GVBD occurs approximately 2 h after the LH surge, and the first polar body can be seen 5 h later [16, 39]. Because NO in the present study did not completely prevent GVBD of cultured denuded oocytes, other inhibitory substances present in follicles or NO derived from the NO donor might be metabolized within a few hours.

In conclusion, iNOS inhibitor as well as hCG induce oocyte meiotic maturation, and NO donor prevents it. Addition of iNOS inhibitor to preovulatory follicles decreases intrafollicular cGMP concentrations. These results suggest that the iNOS-NO-(cGMP) axis may be one of the modulators of oocyte meiotic maturation during the ovulatory process.


   FOOTNOTES
 
1 Correspondence: Yasuhiko Nakamura, Reproductive, Pediatric, and Infectious Science, Yamaguchi University School of Medicine, Minamikogushi 1-1-1, Ube 755–8505, Japan. FAX: 81 836 22 2287; yasu-ygc{at}umin.ac.jp Back

Received: 12 March 2002.

First decision: 8 April 2002.

Accepted: 24 May 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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