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Department of Obstetrics and Gynecology (J.-C.H., J.S.G.), University of Texas Medical School at Houston, Department of Pathology, Baylor College of Medicine (F.A.), University of Texas Medical School at Houston (K.J.T.), Vascular Biology Center (N.M.-A., K.K.W.), Institute of Molecular Medicine and Division of Hematology, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77030
Abstract
Animal studies unequivocally support the indispensable role of prostaglandin (PG) and cyclooxygenase (COX) in ovulation and implantation. Available data also suggest that PG and COX may be important in the transport of embryos. The effects of PGE2 and PGF2
on the contractility of human tubal muscle have been studied extensively; the expression of COX in human fallopian tubes was also reported. Despite all these, two fundamentally important questions remained to be answered: 1) which PGs are produced by human fallopian tubes; and 2) which COX isoform(s) is expressed by the fallopian tubes.
We used reverse-phase HPLC to study the metabolism of [1-14C] arachidonic acid by the fallopian tubes. We found that 6 keto-PGF1, a stable metabolite of prostacyclin (PGI), and PGE2 constituted 56% ± 10% and 35% ± 10% (mean ± SEM, four samples), respectively, of total eicosanoids synthesized. Western blot analysis revealed the expression of both COX isoforms. Immunohistochemistry study showed that both COX-1 and -2 were localized to nonciliated epithelia and tubal smooth muscle. In addition, COX-2 was also expressed in ciliated epithelial cells. Western blot analysis revealed the expression of PGI synthase (PGIS) and PGI receptor by fallopian tubes. Immunohistochemistry confirmed the expression of PGIS by luminal epithelia, tubal smooth muscle, vascular endothelial cells, and vascular smooth muscle cells. Iloprost, a PGI analog, inhibited the activities of circular and longitudinal muscles of the fallopian tube. Thus, the fallopian tube expresses both COX isoforms and PGIS. Furthermore, it is a source and a target of PGI. PGI and COX may be important to gamete function, embryo transport, and embryo development.
WITHIN 24 HOURS OF ovulation, the human egg is fertilized in the distal end of the fallopian tube. It is 3–4 d later that the embryo arrives at the uterus and prepares for implantation (1). Thus, the fallopian tube provides an environment for sperm and egg interaction and early embryo development. The transport of embryos is aided by the contraction and the relaxation of circular and longitudinal smooth muscles surrounding the human fallopian tube (2). Contractility of smooth muscles is regulated by myriad factors, including ß-adrenergic nerves (3), sex steroids (3, 4, 5, 6), nitric oxide (7, 8, 9), prostaglandins (PGs) (10, 11, 12, 13), and others. It was shown that different PGs had distinct effects on tubal smooth muscle in vitro (10, 14). Whereas PGF2 increased the contractility of tubal muscle, PGE2 elicited different responses: inhibition of the circular muscle, and inhibition and stimulation of the longitudinal muscle at low or high concentrations, respectively (10). Although earlier studies showed that human fallopian tubes produced PGE2 and PGF2 (15), it remained unclear whether other PGs are produced by the fallopian tubes and, if so, in what proportions.
Cyclooxygenase (COX, also known as PG H synthase, PGHS) catalyzes the biosynthesis of PGH2, a precursor for all PGs (16). COX has two isoforms: COX-1 and -2. The expression of the former is ubiquitous, the latter occurs on induction (17). In 1990, before the discovery of COX-2 (18), COX was detected in nonciliated epithelial cells of human fallopian tubes (19). It is not clear whether the human fallopian tube expresses both COX isoforms and, if so, in which cell type(s).
To gain insight into fallopian tube PG biosynthesis, we determined arachidonic acid (AA) metabolism (by HPLC) and enzyme expressions (by Western blots and immunohistochemistry). We found that prostacyclin (PGI) (also known as PGI2) and PGE2 were the major products. We detected both COX isoforms and PGI synthase (PGIS) in the fallopian tubes. Immunohistochemical examination showed localization of both COX-1 and -2 to nonciliated epithelial cells and tubal smooth muscle cells. However, COX-2 was also expressed in ciliated epithelial cells. COX-2 in the fallopian tube was functionally active, because NS-398, a specific COX-2 inhibitor, decreased the metabolism of [1-14C] AA by 66%. Further studies showed that the fallopian tube expressed PGI receptor (IP) and responded to iloprost, a stable PGI analog.
Materials and Methods
Materials
Unless specified otherwise, all chemicals were purchased from Sigma (St. Louis, MO). The recombinant human COX-2 was a gift from Dr. Kulmacz; the ovine COX-1, from Dr. A.-L. Tsai; and the recombinant human PGIS and affinity-purified peptide antibodies for PGIS and IP, from Dr. K.-H. Ruan (the Division of Hematology, Department of Internal Medicine, University of Texas Health Science Center at Houston). Segments of fallopian tubes were obtained from patients undergoing postpartum tubal ligation (within 18 h of delivery) or hysterectomy (for benign conditions unrelated to fallopian tubes). Samples were placed on ice and brought to the laboratory immediately. Depending on the nature of the experiment, they were used immediately, stored at -70 C for future processing, or fixed in 10% formaldehyde. Microsomes, prepared from frozen samples, were used in some experiments; and fresh tissues, minced into pieces (
1 x 1 mm) were used in others. For experiments on muscle contractility, tubal smooth muscle from the ampullo-isthmic junction was used. The phases of the menstrual cycle were based on the histological dating of the endometrium. We have permission from our institutional review board to conduct this project.
Microsomes preparation
Fallopian tubes were homogenized in 2 ml homogenization buffer (50 mM Tris HCl, pH 8.0; 2 mM EDTA; 0.25 M sucrose) containing protease inhibitors (1 mM 4-(2-aminoethyl)benzene sulfonyl fluoride hydrochloride, 0.8 µM aprotinin, 50 µM betastatin, 15 µM E-64, 20 µM leupeptin hemisulfate, 10 µM pepstatin A) using a tissue homogenizer (Tissumizer; Tekmar Co., Cincinnati, OH). The homogenate was first centrifuged (10,000 x g) at 4 C for 10 min. The supernatant was further centrifuged (100,000 x g) at 6 C for 50 min. The pellet was homogenized in a resuspension buffer (50 mM Tris HCl, pH 8.0; 2 mM EDTA; 1 mM diethyldithiocarbamate; 0.5 mg/ml tryptophan) using a hand-held tissue homogenizer. Aliquots were used immediately for PG synthesis experiments or stored at –70 C until Western blot analysis. The protein concentrations were determined using BSA as standards (Micro BCA; Pierce Chemical Co., Ann Arbor MI).
Eicosanoid profile
The metabolites of [1-14C] AA were analyzed by reverse-phase HPLC according to a procedure described previously (20). Briefly, minced tissue (1 mm x 1 mm) or aliquots of microsomes prepared from fallopian tubes were resuspended in 250 µl incubation buffer (50 mM Tris HCl, pH 8.0; 2 mM EDTA; 1 mM glutathione; 1 mM tryptophan) containing 20 µM [1-14C] AA (56 mCi/mmol, 50 µCi/ml; Amersham Pharmacia Biotech, Piscataway, NJ) and placed in a 37-C water bath for 30 min. The supernatant was extracted (Sep-Pak cartridges C18; Waters Corp., Milford, MA), and the eicosanoids were detected using HPLC (Waters Corp.) with an in-line radio-detector (ß-Ram; Inus Systems Inc., Tampa, FL). The retention time of each eicosanoid was determined by individual standard in previous experiments. The data were acquired and analyzed using Millennium 32 software (Waters Corp.). To confirm that COX-2 was functionally active, parallel experiments were performed in which aliquots of the minced tissue were preincubated with NS-398 (5 µM; Cayman Chemical Co., Ann Arbor, MI) for 30 min before receiving [1-14C] AA.
Western blot analysis
Microsomal samples from fallopian tubes were used for Western blot analysis according to methods described previously (21). Briefly, proteins (20 µg/lane) were separated using a 10% acrylamide gel and transferred to a 0.45-µm nitrocellulose membrane (Schleicher \|[amp ]\| Schuell, Inc., Keene, NH). Mouse monoclonal antibodies against unique human COX-1 and -2 sequences (Cayman Chemical Co.) were used to detect respective COX isoform; rabbit polyclonal antibodies against peptide sequence of human PGIS and IP were used to detect PGIS and IP receptor, respectively. To visualize the antibody retained on the membrane, enhanced chemifluorescence (Amersham Pharmacia Biotech) was used according to manufacturer’s protocols. The fluorescence signals were detected using a laser scanner (Molecular Dynamics Storm 850, Amersham Biosciences Corp., Piscatway, NJ). To confirm the specificity of COX-1 and -2 antibodies, ovine COX-1 and recombinant human COX-2 were loaded in separate lanes next to the samples.
Immunohistochemistry
Immunohistochemical localization of COX-1, COX-2, and PGIS was performed according to methods described previously (22). Briefly, paraffin-embedded sections were deparaffinized and rinsed well with double-distilled water. The sections were heated to 100 C in Tris-EDTA buffer (1 mM and 0.1 mM, respectively), for 45 min, using a Black and Decker steamer (Towson, MD). After cooling down, the sections were rinsed in double-distilled water and blocked with 3% H2O2 for 15 min. The remaining steps were carried out manually at room temperature, with PBS rinse between steps. The sections were blocked for 5 min using Power Block (BioGenex Laboratories, Inc., San Ramon, CA) followed by 15 min each of avidin and biotin block (Vector Laboratories, Inc., Burlingame, CA). After a 2-h incubation with primary antibody (same antibodies used in Western blot analysis; 1:200 dilution), the sections were incubated with secondary antibody (MultiLink; BioGenex Laboratories, Inc.) and horseradish peroxidase conjugate, each for 20 min. After the final incubation with substrate (AEC, 3-amino-9-ethylcarbazole; BioGenex Laboratories, Inc.) for 15 min, the sections were counterstained with hematoxylin. Preimmune serum was used for negative controls.
Muscle contraction experiment
A muscle contraction experiment in organ chambers was set up according to methods described previously (23). Strips of longitudinal and circular muscle of fallopian tubes were dissected from the ampullo-isthmic junction, which was identified by advancing a blunt probe (1.5 mm) from the fimbrial end until resistance was met (10). The muscle strips were placed in organ chambers filled with Krebs-Ringer solution (NaCl, 136 mM; KCl, 4.7 mM; CaCl2, 2.5 mM; MgCl2, 1.5 mM; NaH2PO4, 1.8 mM; NaHCO3, 31.5 mM; glucose, 0.015 mM) heated to 37 C and oxygenated with 95% O2-5% CO2. The muscle strips, under a tension equivalent to a load of 1.0 g, were attached to isometric transducers. The contractions were recorded using a polygraph recorder (Polygraph Model 7; Grass Instrument, Quincy, MA).
Results
We obtained 14 fallopian tubes to prepare microsomes: 5 from postpartum patients, 4 from patients in luteal phase, and 5 from patients in follicular phase. The microsomes were used to study the eicosanoid files and the expression of COX-1, COX-2, PGIS, and IP (details below). Another 5 fallopian tubes were used to study eicosanoid profiles of minced fallopian tube: 2 from postpartum patients and 1 of each from patients in the luteal phase and the follicular phase. Four additional fallopian tubes (2 of each from patients in follicular and luteal phases) were microdissected to separate smooth muscle and luminal epithelium to study their eicosanoid profiles. Eighteen fallopian tubes in paraffin blocks (6 of each from postpartum, follicular, and luteal phase patients) were used for immunohistochemistry study.
PGI and PGE2 were the major PGs produced by human fallopian tubes
We first determined the metabolites of [1-14C] AA using microsomes prepared from fallopian tubes. We found keto-PGF1, a stable metabolite of PGI, and PGE2 were the major metabolites constituting 89.4% ± 7.1% and 9.6% ± 7.1% (mean ± SEM, five samples), respectively, of total eicosanoids synthesized (Fig. 1a
). Profiles from five microsomes samples were similar (two from postpartum patients, one from a patient in follicular phase, and the other two from the secretory phase of the menstrual cycle). [1-14C] AA metabolite profile of minced fallopian tubes (two from postpartum patients, one each from patients in follicular and secretory phase of the menstrual cycle) revealed a larger quantity of PGE2 than that from microsomal preparations (Fig. 1b). The stable metabolite of PGI (6-keto-PGF1) and PGE2 constituted 56% ± 10% and 35% ± 10% (mean ± SEM), respectively, of eicosanoids synthesized by minced fallopian tubes (Fig. 1b). Thromboxane A2 and other PGs each represented less than 5% of total eicosanoids.
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, c and d). Human fallopian tube expressed both COX isoforms, which had distinctive cellular distribution
To positively differentiate COX-2 from COX-1 in Western blot analysis, we loaded ovine COX-1 and recombinant human COX-2 next to microsomal samples prepared from human fallopian tubes (5 from postpartum patients, 4 from follicular phase, and 5 from the luteal phase of the menstrual cycle). The membranes were then probed with specific COX-1 or COX-2 monoclonal antibody. We detected both COX isoforms in all 14 samples (Fig. 2).
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, c–d, and g–h, respectively) and smooth muscle cells (Fig. 3, a–d, and e–h, respectively). Only COX-2 was expressed in ciliated cells (Fig. 3, g–h). The luminal epithelia had more staining than the smooth muscle; longitudinal muscle had slightly more staining than the circular muscle (Fig. 3, a–b, and e–f, for COX-1 and -2, respectively). The findings were confirmed in all 18 samples examined (follicular phase, luteal phase, and postpartum, 6 samples each). We did not observe any difference in intensities among the 3 groups.
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To determine whether COX-2 was functionally active, we performed parallel experiments on minced samples from the same fallopian tube. One sample underwent a 30-min incubation with NS-398, the other with vehicle, before receiving [1-14C] AA. NS-398 reduced the metabolism of [1-14C] AA by 66% (Fig. 4).
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Because PGIS catalyzes PGI formation, we performed Western blot analysis of PGIS on microsomal samples from 2 fallopian tubes (1 from a patient in the follicular phase and 1 from a patient in the luteal phase of the menstrual cycle). PGIS was present in both samples (Fig. 2). Immunohistochemistry studies showed PGIS in luminal epithelial cells, tubal smooth muscle cells, vascular endothelial cells, and vascular smooth muscle cells (Fig. 3, i–k). Vascular endothelial cells, vascular smooth muscle cells, and the luminal epithelia had more staining than tubal smooth muscle. Similar to the distribution of COX-2 in the luminal epithelia, PGIS was localized in both ciliated and nonciliated cells. The findings were confirmed in all 18 samples examined (follicular phase, luteal phase, and postpartum, 6 samples each). There was no observable difference in staining intensities among the 3 groups.
Tubal smooth muscle is a target of PGI
Given the well-known effects of PGI on vascular smooth muscle, the above findings prompted us to conduct further experiments to determine the effects of PGI on tubal smooth muscle. First, we performed Western blot analysis on microsome samples from fallopian tubes (luteal and follicular phase, two each) to confirm the presence of IP. Next, we placed strips of longitudinal and circular muscle in organ chambers and studied how PGI affected their contractions. Western blot analysis showed the expression of IP by the fallopian tube (Fig. 5a). Iloprost (1 µM), a stable analog of PGI, abolished the spontaneous contractions exhibited by both longitudinal and circular muscle (Fig. 5b). The loss of contractility was not caused by cell death, because calcium ionopher A 23187 (2 µM) restored the contractions (data not shown).
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Our findings reveal, for the first time, that human fallopian tubes express PGIS as well as COX-1 and -2, and synthesize abundant PGI. PGI was produced by luminal epithelia and tubal smooth muscle. PGE2 was also synthesized in large quantity, primarily by the luminal epithelia. PGE2 is converted from PGH2 by PGE synthase, which has two isoforms: a membrane-bound (24) and a cytosolic isoform (25). Because microsomes produced relatively less PGE2 than the minced fallopian tube (Fig. 1, a vs. b), it may be assumed that most of the PGE2 produced by epithelial cells was catalyzed by the cytosolic isoform of PGE synthase.
Immunohistochemistry studies indicated that COX-1 and COX-2 were constitutively expressed in luminal epithelial cells and colocalized with PGIS. It has been suggested that colocalization of COX-1 or -2 with PGIS to the endoplasmic reticulum of vascular endothelial cells provided a functional coupling of the two enzymes that facilitate the biosynthesis of PGI (26). We suspect that a similar functional coupling takes place in the luminal epithelia of the fallopian tube.
PGI relaxes vascular smooth muscle via IP receptor, which activates adenyl cyclase and elevates intracellular cAMP (27). In this study, we found that fallopian tube smooth muscle cells exhibited properties similar to those of vascular smooth muscle cells: they expressed IP and relaxed when treated with stable analog of PGI. Thus, PGI acts in a paracrine manner and is likely to play an important role in transporting fertilized eggs and cleaving embryos.
PGI, unlike PGE2 and PGF2, was never seriously considered to be a product of the fallopian tube (11). The three reports studying the effects of PGI on tubal muscle activity did not come to the same conclusion (11, 12, 28). The observed relaxation effect of PGI on tubal smooth muscle in our study is consistent with the relaxation effect of cAMP on tubal smooth muscle (13) and the signaling pathway of IP receptor (27).
The journey of human embryo in the fallopian tube consists of a relatively quick passage through the distal tube, a delay for 2–3 d in the proximal ampulla, and a rapid transit through the isthmus (29). The ampullo-isthmic junction in rabbits has a sphincter function (30, 31), which controls the movement of embryos. Indirect evidence suggests a similar physiologic sphincter in the human fallopian tube that is regulated by adrenergic innervation (32, 33), steroid hormones (34), and PGs (10). Factors responsible for rapid transit through the isthmus have not been delineated. We speculate that PGI may play an important role in the initiation of rapid transit of embryo through the isthmus of the fallopian tube. mRNA for human chorionic gonadotropin (hCG) can be detected in human embryo at a time when the rapid transit through the physiological sphincter occurs, i.e. 2–3 d after fertilization (6–8 cell stage) (35). Because hCG increases COX-2 mRNA and protein expression in cultured tubal luminal epithelia (36), the resultant increase in PGI may be the key that opens the sphincter at the ampullo-isthmic junction. Furthermore, the endogenous hCG from the fallopian tube may also participate in this event (37).
The performance of gametes and the development of embryos may also be affected by PGI diffused into the tubal lumen from the luminal epithelia. Although PGI has traditionally been considered as a molecule of the cardiovascular system (38), recent observations on gene knockout mice suggest that PGI is indispensable in other physiological functions, such as embryo implantation (39) and pain sensation (40, 41). Indeed, low seminal PGI was associated with decreased sperm motility (42).
PGE2 may also be involved in embryo transport and the functions of gametes. Via a novel membrane receptor, PGE2 induces acrosome reaction in the sperms (43). The contractions of circular and longitudinal tubal muscle are inhibited and stimulated, respectively, by PGE2 (11). There are four PGE2 receptor (EP) isoforms with different signaling pathways: EP2 and EP4 increase cAMP, EP3 decreases cAMP, and EP1 increases phospholipase C activity. The differential response to PGE2, demonstrated by longitudinal and circular tubal smooth muscle, suggests distinctive EP expressions in these muscle cells.
We found that COX-2 is constitutively expressed in luminal epithelia and the tubal smooth muscle. Our findings suggest that COX-2 may serve physiological functions in the human fallopian tube. Unlike the previously held belief that COX-2 is only involved in pathological processes, recent evidence suggests that COX-2 may have physiological functions: COX-2 is constitutively expressed in the kidney (44), brain (45), and stomach (46). However, the factor(s) that induces its expression remains to be explored.
The expression of COX-2, but not COX-1, in ciliated luminal epithelia may be related to the distinct biology of COX isoforms proposed by Smith et al. (47) COX-1, localized in the endoplasmic reticulum, synthesizes PGs, which are secreted and act locally in a paracrine fashion. COX-2, localized in the endoplasmic reticulum and inner membrane of the nuclear envelope, synthesizes PGs that act in paracrine and autocrine fashions, respectively. The former augments the functions of COX-1; the latter, acting through the nucleus, regulates cell differentiation and replication. Thus, nonciliated cells express only COX-1 to serve their role as secretory cells; ciliated cells express both COX-1 and –2 to serve their role in the ovum pick-up and the embryo transport (48).
Indomethacin, a nonselective COX inhibitor, has been used to investigate the effects of PGs on tubal motility. Indomethacin has been shown to increase (49), decrease (50), or have no effect (51) on tubal motility. Because none of the studies measured the endogenous PGs or the conversion of radiolabeled AA by the fallopian tubes, the extent of COX inhibition cannot be ascertained. Most of the over- the-counter nonsteroidal antiinflammatory agents block both COX-1 and COX-2. The safety of these agents in women desiring pregnancy may need to be reevaluated.
In summary, the human fallopian tube expresses COX-1, COX-2, PGIS, and IP. It is the source and the target of PGI. PGI may serve physiological functions in the human fallopian tube, such as the transport of gametes and embryo. It may also affect the development of preimplantation embryos.
Acknowledgments
We thank Dorene M. Rudman, certified histotechnician, American Society of Clinical Pathology, Texas Children’s Hospital, for technical assistance; Dr. Norman Weisbrodt for assistance in setting up an organ chamber for experiments; and Mary Carson for secretarial assistance.
Footnotes
Address all correspondence and requests for reprints to: Jaou-Chen Huang, M.D., Department of Obstetrics and Gynecology, University of Texas Medical School, 6431 Fannin Street, MSB 3.604, Houston, Texas 77030. E-mail: .
This work was supported in part by NIH Grants NS-23327 and HL-50675 (to K.K.W.) and was presented in part at the 57th Annual Meeting of the American Society for Reproductive Medicine, Orlando, Florida, 2001. J.-C.H. is a Women’s Reproductive Health Research scholar (Grant HD-01277).
J.-C.H. and F.A. contributed equally to this manuscript.
Present address for K.J.T.: Department of Obstetrics and Gynecology, St. Joseph Hospital, 1819 Crawford, Suite 1708, Houston, Texas 77002.
Abbreviations: AA, Arachidonic acid; COX, cyclooxygenase; EP, PGE2 receptor; hCG, human chorionic gonadotropin; IP, PGI receptor; PG, prostaglandin; PGHS, PG H synthase; PGI, prostacyclin; PGIS, prostacyclin synthase.
Received February 8, 2002.
Accepted May 24, 2002.
References
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