Molecular Human Reproduction, Vol. 7, No. 11, 1057-1063,
November 2001
© 2001 European Society of Human Reproduction and Embryology
Uterine physiology |
Localization and role of endothelin-1 and endothelin receptors in the human Fallopian tube
1 Department of Comprehensive Reproductive Medicine and 2 Institute of Biomaterials and Bioengineering, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
Abstract
The present experiments were designed to investigate the localization and role of endothelin-1 (ET-1) and endothelin receptors (ETA and ETB) in human Fallopian tubes obtained from patients in the follicular phase. Immunohistochemical studies revealed the predominant localization of ET-1 and of ETB receptors in the tubal epithelium and also within the muscle layer to a lesser degree. ETA receptors were dominant within the muscle layer. Scatchard plot analysis of the [125I]ET-1 binding also revealed the localization of ETA and ETB receptors on the Fallopian tubal membrane. A dissociation equilibrium constant of 34.6 ± 3.3 pmol/l and a maximum binding site concentration of 1137.0 ± 239.1 fmol/mg protein were obtained from the Scatchard plot analysis. Treatment of Fallopian tubal strips with ET-1 produced a tonic contraction which was inhibited by an ETA antagonist but not by an ETB antagonist. However, the increase in frequency and decrease in amplitude of rhythmic contractions caused by ET-1 were modulated by the ETB antagonist but remained unaffected by the ETA antagonist. These results suggest that ET-1 modulates the motility of the Fallopian tube through excitation of ETA and/or ETB receptors and possibly plays some role in oocyte capture.
endothelin-1/endothelin receptors/Fallopian tube/oocyte capture/tonic contraction
Introduction
Endothelin-1 (ET-1) is the most potent vasoconstrictive peptide originally isolated from the supernatant of cultured porcine endothelial cells (Yanagisawa et al., 1988
). However, it is now known that the peptide is produced in many tissues and in different cell types including those in the reproductive system such as endometrial stromal (Kubota et al., 1995), glandular epithelial cells (Economos et al., 1992; Marsh et al., 1994) and ovarian granulosa cells (Kamada et al., 1992, 1993). In terms of the roles of ET-1 in the reproductive system, contraction of the myometrium during parturition (Word et al., 1990; Sakamoto et al., 1997, 1999), cessation of menstrual bleeding and endometrial regeneration and remodelling during the menstrual cycle (Salamonsen et al., 1999) have been described. Moreover, ET-1 may be involved in early embryo development through its activity as one of the growth factors (Battisitini et al., 1993; Stjernquist, 1998).
The Fallopian tube provides the optimum environment for the fertilization process, the development of early embryos (Sayegh and Mastroianni, 1991) and the transportation of embryos to the uterus at the best time for implantation (Halbert et al., 1976; Pulkkinen et al., 1995); these functions of the Fallopian tube are under the direct control of the endocrine system (Zenteno et al., 1989), autonomic nervous system and/or locally produced humoral factors (Perez-Martinez et al., 1998); however, the detailed regulation mechanisms have not been fully elucidated. In particular, little has yet been described about the contribution of the smooth muscle motility of the Fallopian tube to oocyte capture.
We have previously reported that the concentration of ET-1 in human follicular fluid obtained during an IVF–embryo transfer programme is relatively high. It was therefore predicted that ET-1 might play some physiological role in follicular development (Kamada et al., 1993). Furthermore, the Fallopian tube will be exposed to a high concentration of ET-1 at the time of ovulation. In the case of bovine oviduct, it has been demonstrated that cultured tubal epithelium produces ET-1, and the peptide induces contraction of tubal strips (Rosseli et al., 1994a,b). These reports lead us to predict that ET-1 derived from the follicular fluid or tubal epithelium contributes to the induction of contraction of the human Fallopian tubes and may play some role in oocyte capture. Although two distinct ET receptor subtypes, ETA and ETB, exist in many tissues (Arai et al., 1990; Sakurai et al., 1990), there have been no reports about the localization of ET receptors and their classification in the Fallopian tube. Therefore, the present experiments were designed to investigate the localization and role of ET-1 and ETA and ETB receptors in the human Fallopian tube. We selected the ampullar segments from the follicular phase as materials to investigate the possible mechanisms of oocyte capture by the Fallopian tube.
Materials and methods
Chemicals
The following chemicals were used: ET-1 (human) (Protein Research Foundation, Osaka, Japan), aprotinin, leupeptin, pepstatin A and bovine serum albumin (BSA; fraction V) (Sigma, St Louis, MO, USA), [125I]ET-1 (specific activity 81.4 TBq/mmol) (NEN®; Life Science Products, Boston, MA, USA), cis-2,6-dimethylpiperidinocarbonyl-g-methylleucyl-D-Trp(1-CO2CH3)-D-Nle-OH (BQ788), a selective antagonist for ETB receptor subtype (Ishikawa et al., 1994) (Novabiochem, Läufelfingen, Switzerland), anti-human ET-1 rabbit antiserum (Peptide Institute, Osaka, Japan), anti-human ETA receptor rabbit IgG and anti-human ETB receptor rabbit IgG (IBL, Gunma, Japan). Cyclo(D-Asp-L-Pro-D-Val-L-Leu-D-Trp-) (BQ123), a selective antagonist for ETA receptor subtype (Ihara et al., 1992), was synthesized and generously donated by the Chemical Research Department, Teikoku Hormone Manufacturing, Tokyo, Japan.
Subjects and tissue collection
Ethical approval was obtained from the Ethics Committees of Tokyo Medical and Dental University before commencement of the study. Twenty-four Fallopian tubes were obtained from 15 women undergoing surgery for routine benign gynaecological indications (leiomyoma, n = 13; adenomyosis, n = 1; carcinoma in situ, n = 1). Only patients with regular menstrual cycles who were in the follicular phase were included in the present experiments. They were otherwise healthy, normotensive and were not taking any drugs. The follicular phase was determined on the basis of the cycle days, macroscopic findings of the ovaries during the operations and, in some cases, levels of serum oestradiol, progesterone and LH. The patients' ages ranged from 32–50 years old with a mean value of 42.3. The patients had given their informed consent for the present study. Immediately after excision, the tissues were transferred into oxygenized and ice-cold modified Krebs solution [NaCl 115.0, KCl 4.7, MgSO4 7H2O 1.2, CaCl2 2H2O 2.5, KH2PO4 1.2, NaHCO3 25.0 and glucose 10 (mmol/l)] for the measurement of mechanical responses. Nine specimens from the ampullar portion were cut to a size of 5–10 mm and fixed in 10% neutral formalin for 48 h for immunohistochemistry. Four additional specimens were frozen in liquid nitrogen after removing the serosa and stored at –80°C until use in the receptor binding assay.
Immunohistochemical studies
To examine the localization of ET-1, and ETA and ETB receptor subtypes, a transverse ampullar segment, which had been fixed in 10% neutral formalin, was embedded in paraffin, sliced into 6 µm thick sections with the aid of a microtome and mounted on silane-coated slides. The sections were deparaffinized and hydrated. Then 10% normal goat serum was applied for 20 min, followed by incubation at 4°C overnight with primary rabbit antisera against ET-1 [diluted 1:2000 in phosphate-buffered saline (PBS)] (cross-reactivities against ET-2 and ET-3 were 60 and 40% respectively, based on data from the product company), or with rabbit antibodies against ETA receptor (2 µg/ml) or ETB receptor (2 µg/ml). After washing three times with PBS, the preparations were incubated with biotinylated goat anti-rabbit antibody for 30 min, washed with PBS, and followed by treatment with the avidin–alkaline phosphatase complex (Vectastain® ABC-AP; Vector Laboratories, Burlingame, USA) for 30 min. The sections were then incubated with Vector® Red (Vector Laboratories), until the adequate stain intensity was attained from the highly fluorescent reaction products. After counterstaining with haematoxylin, the sections were dehydrated and mounted with malinol (Muto Pure Chemicals Ltd, Tokyo, Japan).
Preparation of crude membrane fractions
Crude membrane fractions were prepared according to the method described previously (Azuma et al., 1994). Briefly, Fallopian tube specimens were minced with scissors and homogenized in a Polytron at maximum speed for 20 s to a 17% homogenate in buffer A (20 mmol/l HEPES, 250 mmol/l sucrose, 5 mmol/l EGTA, 3 µg/ml leupeptin, 2 µg/ml aprotinin, 3 µg/ml pepstatin A, pH 7.4). The homogenate was centrifuged at 1200 g for 20 min at 4°C. The supernatant was removed and centrifuged at 80 000 g for 60 min at 4°C. The resulting pellet was re-suspended in buffer A as a crude membrane fraction and stored at –80°C until use. Protein concentration was determined with the micro BCA kit (Pierce, Rockford, IL, USA).
Radioligand receptor binding assay
The radiolabelled ligand used for saturation analysis was [125I]ET-1. The crude membrane fraction (50 µl containing 15 µg protein) was added to 50 µl of buffer B (30 mmol/l HEPES, 150 mmol/l NaCl, 5 mmol/l MgCl2, 1 mg/ml BSA) and 100 µl of [125I]ET-1 at eight different concentrations of 5.47 to 700 pmol/l and shaken for 120 min at 25°C. After addition of 3 ml of ice-cold buffer B, the mixture was filtered under reduced pressure through a Whatman GF/B glass-fibre filter (Whatman, Maidstone, Kent, UK) to separate free and bound [125I]ET-1. After two washes with 3 ml of buffer, the filters were transferred into counter tubes. Radioactivity was determined in a 
-counter (Auto-Gamma 800C; Packard, Meriden, CT, USA). Specific binding was defined as the total binding minus non-specific binding measured in the presence of 125 nmol/l unlabelled ET-1. Displacement of the specific binding of [125I]ET-1 (25 pmol/l) was performed with ET-1 (3x10–12 to 10–7 mol/l), BQ123 (3x10–10 to 10–5 mol/l), BQ788 (3x10–10 to 10–5 mol/l) and BQ123 plus BQ788.
Measurement of mechanical responses
The mechanical responses were measured according to the methods described previously (Azuma et al., 1992). Fallopian tubes were dissected vertically along the side of the mesosalpinx and opened. After the serosa was removed, longitudinal strips 2 mm in width and 7 mm in length comprising the tubal epithelium and the smooth muscle layer were prepared under a binocular stereoscope. The strips were mounted vertically in an organ chamber containing 5 ml of modified Krebs solution, which was continuously bubbled with 95% O2 and 5% CO2 at 37°C. One end of each strip was secured to the bottom of the organ chamber, and the other was attached to a force-displacement transducer (TB-611T: Nihon Kohden Kogyo Co., Tokyo, Japan). Isometric tension changes were recorded on a pen-writing oscillograph (R-64; Rikadenki Kogyo Co., Tokyo, Japan). Before beginning the experiments, strips were allowed to equilibrate for at least 60 min in the bathing solution and during this period the bathing solution was replaced every 20 min with fresh solution. In the preliminary experiments, the magnitude of contraction in response to 3x10–8 mol/l ET-1 was compared under resting tensions of 400, 800, 1200 and 1600 mg. Since the contractile response was greatest and well reproducible under the resting tension of 1200 mg, in the following experiments, the length of strips was adjusted several times until a stable tension of 1200 mg was attained. After 5–10 min, a spontaneous rhythmic contractile activity was established. In order to obtain the reference contraction, 60 mmol/l KCl was added and the bath was washed with fresh solution. After the stable resting tension was regained, ET-1 was applied in a cumulative manner (3x10–11 to 3x10–8 mol/l) and a concentration–response curve was constructed in the absence or presence of 3x10–6 mol/l BQ123, as an ETA antagonist (Ihara et al., 1992), 3x10–6 mol/l BQ788, as an ETB antagonist (Ishikawa et al., 1994), or a combination of both. Each antagonist was added 20 min before the application of ET-1. ET-1-induced contractions were assessed by maximum changes in the resting tone, amplitude of rhythmic contraction (measured at 15 min after adding ET-1) and frequency of rhythmic contractions (the number of rhythmic contractions between 5 and 15 min after adding ET-1). Changes in the resting tone and amplitude of rhythmic contractions were given as a percentage of 60 mmol/l KCl-induced contractions.
Statistical analysis
All data are presented as mean ± SEM. The statistically significant differences between two means were determined by one-way analysis of variance (ANOVA) or repeated measures ANOVA. Differences were considered to be significant at P < 0.05.
Results
Immunohistochemical localization of ET-1 and ET receptors
ET-1 immunoreactivity, histochemically visualized as a red fluorescence, was observed mainly in the tubal epithelium and was relatively weak in the smooth muscle layer (Figure 1a and b). ETA and ETB receptor immunoreactivities were seen in both the smooth muscle layer and tubal epithelium. ETA signals were detectable predominantly in the smooth muscle layer (Figure 1d and e), while ETB signals were stronger in the tubal epithelium than in the smooth muscle layer (Figure 1g and h). The same results were obtained by using peroxidase and DAB (3,3'-diaminobenzidine tetrahydrochloride) (Dako, Kyoto, Japan) (data not shown).
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Radioligand receptor binding assay
The [125I]ET-1 binding was saturated with high affinity. Scatchard plot analysis revealed that the binding sites of [125I]ET-1 constituted a single population. The dissociation equilibrium constant (Kd) and receptor density (Bmax) values were determined to be 34.6 ± 3.3 pmol/l (n = 4) and 1137.0 ± 239.1 fmol/mg protein (n = 4) respectively (Figure 2a
). In the displacement experiments, unlabelled ET-1 and the combination of BQ123 with BQ788 inhibited the specific [125I]ET-1 binding in a concentration-dependent manner (Figure 2b). Complete inhibition was attained at a concentration of 10–7 mol/l of unlabelled ET-1 and 10–6 mol/l of the combination of BQ123 and BQ788. BQ788, at a concentration range of 10–9 to 10–7 mol/l, did not produce a significant inhibition of the specific [125I]ET-1 binding, but, at the highest concentration of 10–5 mol/l, the antagonist completely inhibited the specific binding. In contrast, the [125I]ET-1 binding was inhibited by concentrations of 10–8 to 10–6 mol/l of BQ123 but was not fully inhibited by BQ123 even at the highest concentration of 10–5 mol/l (Figure 2b).
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), BQ123 (
), BQ788 (
) and combination of BQ123 with BQ788 (
).Mechanical responses to ET-1
The longitudinal strips of the ampullar portion of the Fallopian tube exhibited regular spontaneous rhythmic contractions under 1200 mg tension. Similar phenomena were observed in the transverse strips (data not shown). Treatment with KCl (60 mmol/l) induced transient contractions and abolished rhythmic contractions (Figure 3a
). When ET-1 at concentrations of 3x10–9 to 3x10–8 mol/l was applied, tonic contraction and changes in the amplitude and frequency of the rhythmic contractions could be observed (Figure 3b). As shown in Figure 4, ET-1 (3x10–10 to 3x10–8 mol/l) produced tonic contractions in a concentration-dependent manner (n = 9), and these were significantly (P < 0.05: repeated measures ANOVA) inhibited by an ETA receptor-selective antagonist, BQ123 (3x10–6 mol/l) (n = 7). However, pretreatment with an ETB receptor antagonist BQ788 (3x10–6 mol/l) significantly (P < 0.05: repeated measures ANOVA) enhanced the tonic contraction induced by ET-1 (n = 7). The enhanced contraction with BQ788 was inhibited by combination with BQ123 (n = 5). Furthermore, ET-1 decreased the amplitude and increased the frequency of the rhythmic contractions in a concentration-dependent manner (Figure 5a and b). Since the frequency could not be counted precisely at the highest concentration of 3x10–8 mol/l, these results are not shown in Figure 5b. Only BQ788 affected the changes in rhythmic contractions caused by ET-1, i.e. the decrease in amplitude was inhibited while the increase in frequency was enhanced by 3x10–6 mol/l BQ788. BQ123 showed no effect on the amplitude or frequency of the rhythmic contractions. BQ123 in combination with BQ788 showed only a tendency to affect the rhythmic contractions (Figure 5a and b).
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Discussion
It is well established that Fallopian tubes provide the optimum environment for fertilization, development of early embryos and transportation of embryos to the uterus at the best time for implantation. These functions are considered to be regulated by various humoral (Zenteno et al., 1989) and neural factors (Perez-Martinez et al., 1998). In regard to oocyte capture, it has been explained that the ciliary motion plays an important role, i.e. the minute flow derived from the ciliary beat draws an oocyte, and the cilia pick it up by adhesion (Talbot et al., 1999). Thus, the ciliary movement would bring the oocyte into the tube (Halbert et al., 1989). However, there are often cases of pregnancy where cilia or fimbriae are severely injured. Therefore, the motility of the Fallopian tube could play an additional important role for oocyte capture. On the other hand, the ampullar part of the Fallopian tube has no distinct longitudinal or circular smooth muscle layers and the muscle bundles run randomly (Vizza et al., 1995), suggesting that the ampullar muscle does not produce a peristaltic motility, but produces a spastic contraction in any direction. Moreover, it has been reported that the motility of the ampullar portion dramatically changes around the time of ovulation as compared with the motility of the isthmic portion of porcine (Rodriguez-Martinez et al., 1982a,b) and rabbit (Fredericks et al., 1982) oviducts. Because of the hypothetical importance of Fallopian motility for oocyte capture, we selected the ampullar portion of human Fallopian tubes obtained from patients at the follicular phase.
The present immunohistochemical studies revealed the predominant localization of ET-1 and ETB receptors in the tubal epithelium and of ETA receptors in the smooth muscle layer. Radioligand receptor binding assay also revealed the localization of ETA and ETB receptors in the Fallopian tubal membrane. The receptor displacement study showed that the specific [125I]ET-1 binding was completely inhibited by unlabelled ET-1 and by BQ123 as an ETA receptor antagonist (Ihara et al., 1992) in combination with BQ788 as an ETB receptor antagonist (Ishikawa et al., 1994), but was only partially inhibited by similar concentrations of BQ123 alone. These findings suggest that the ETA receptor is the dominant subtype localized mainly within the muscle layer, while the ETB receptor is a minor subtype, detectable mainly within the epithelium of the Fallopian tube in the follicular phase. Whether or not the ET-1 concentrations in the epithelium, the total number of ET receptors and the ETA/ETB receptor ratio change during the menstrual cycle is of interest in relation to the physiological role of ET-1. Further studies to resolve these issues are progressing in our laboratory.
ET-1 produced a tonic and concentration-dependent contraction of the Fallopian tubal strips. Both the ET-1-induced contraction and the enhanced ET-1-induced contraction with BQ788 were attenuated by BQ123, suggesting the involvement of ETA receptors in producing the tonic contraction. Although the reason why the ET-1-induced contraction was enhanced by BQ788 remains unclarified in the present experiments, there are several possible ways to explain the mechanism. IRL1620 as an ETB-specific agonist (Karaki et al., 1993) does not cause any relaxation in the human Fallopian tube under the resting state or during the contraction produced by U46619 as a stable analogue of thromboxane A2 (S.Sakamoto, unpublished observation). This leads us to assume that the enhancement of the contraction does not result from inhibition of the ETB receptor-mediated relaxation. Although an inhibitor of nitric oxide (NO) synthase has been shown to enhance the ET-1-induced contraction in the bovine oviduct (Rosseli et al., 1994b) and L-arginine causes a relaxation in the human Fallopian tube (Ekerhovd et al., 1997), the L-arginine-induced relaxation remains unaffected by BQ788 (S.Sakamoto, unpublished observation). Therefore, it is unlikely that the ETB receptor indirectly mediates the relaxation by releasing NO in the Fallopian tube. On the other hand, it has been reported that the ETB receptor plays a role in the regulation of the local ET-1 concentration by modulating the clearance of the peptide in the rat lung and rabbit pulmonary artery (Fukuroda et al., 1994; Fukuroda and Nishikibe, 1998). If such a function of the ETB receptor operates in the human Fallopian tube, blockade of ETB receptors would bring about an increase in the effective ET-1 concentration in the vicinity of ETA receptors, which, in turn, would lead to an augmentation of the ET-1-induced contraction. However, further investigations are required to clarify this possibility.
As to the changes in rhythmic contractions caused by ET-1, the increase in frequency was enhanced whereas the decrease in amplitude was inhibited by BQ788. In contrast, BQ123 failed to modify these changes in rhythmic contractions, suggesting that ETB receptors mediate changes in rhythmic contractions caused by ET-1. Although ETB receptors were detectable predominantly in the tubal epithelium, the changes in rhythmic contractions may be mediated by ETB receptors localized at lower concentrations in the muscle layer.
The mechanism of oocyte capture is not yet fully elucidated. However, the finding that the cyclic negative intraluminal pressure of the rabbit tubal ampulla is produced around ovulation by prostaglandin F2
as a constrictor and ß2 adrenoceptor stimulant as a relaxant (Osada et al., 1999) seems to be an attractive explanation, at least in part of the mechanism of oocyte capture; that is, it seems possible to assume that a quick relaxation under the tonic contraction of the tubal ampulla may bring about a negative intraluminal pressure, which, in turn, may introduce an oocyte into the Fallopian tube. In addition, contractions of the mesosalpinx, as well as the Fallopian tube itself, would be important in bringing the fimbria closer to the ovary. Therefore, a relatively high ET-1 concentration in the human follicular fluid (Kamada et al., 1993), the localization of ET-1 and ET receptors, and the capability of ET-1 to cause a tonic contraction with reduced rhythmic activity in the Fallopian tube during the follicular phase, may all be closely related to oocyte capture in cooperation with quick relaxation. The mechanism underlying the quick relaxation should, however, be investigated.
In conclusion, the present immunohistochemical studies revealed the localization of ET-1, and ETA and ETB receptors in the human Fallopian tube. Radioligand receptor binding assays also revealed the localization of ETA and ETB receptors. ET-1 possibly plays an important role for oocyte capture through producing a tonic contraction with reduced rhythmic activity. Further investigations should be performed to clarify, in detail, the physiological role of ET-1.
Notes
3 To whom correspondence should be addressed at: Department of Comprehensive Reproductive Medicine, Graduate School, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo. E-mail: m.sakamoto.gyne{at}tmd.ac.jp 
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Submitted on March 8, 2001; accepted on August 14, 2001.
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