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The Differential Expression of Myometrial Connexin-43, Cyclooxygenase-1 and -2, and G_s Proteins in the Upper and Lower Segments of the Human Uterus during Pregnancy and Labor¹

Department of Obstetrics and Gynecology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom NE1 4LP; and the Maternal and Fetal Medicine Section, Institute of Medical Genetics (F.L.), Yorkhill, Glasgow, United Kingdom G3 8SJ

Address all correspondence and requests for reprints to: Dr. G. Nicholas Europe-Finner, Department of Obstetrics and Gynecology, University of Newcastle upon Tyne, Royal Victoria Infirmary, 4th Floor Leazes Wing, Newcastle upon Tyne, United Kingdom NE1 4LP.

	Abstract

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There is evidence from many studies indicating that a number of specific quiescent and contractile associated proteins are temporally regulated in the myometrium during pregnancy. In this present investigation we provide data that strongly suggest that myometrial connexin-43, cyclooxygenase-1 and -2 (COX-1 and -2), and G_s proteins are also spatially expressed within the human uterus during pregnancy and labor. Using paired lower and upper segment myometrial samples taken from individual women at term and during spontaneous labor, we have measured the expression of these proteins by immunoblotting with specific antibodies. We report that the myometrial gap junction connexin-43 protein is expressed at much greater levels in the upper uterine compared to the lower uterine segment and that this difference is even more pronounced during the course of labor. Conversely, myometrial COX-1 and -2 proteins appear to be expressed at much greater levels in the lower compared to the upper uterine segment. Moreover, the level of expression of both proteins is unaffected by the onset of parturition. In contrast, myometrial G_s protein appears to be uniformly expressed in both lower and upper segments and is similarly down-regulated during parturition, as previously reported. The differential expression of COX-1 and -2 and connexin-43 in the uterus may allow cervical ripening before and dilatation during labor and facilitate effective propagation of contractions from fundus to cervix, which may be further facilitated by the down-regulation of G_s at the onset of parturition.

	Introduction

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THERE is now extensive data from both human and animal studies to suggest that the expression of a range of specific quiescent and contractile myometrial proteins is temporally regulated so as to enable the efficient switch from uterine quiescence to activation at term. For instance, hCG/LH receptors and the adenylyl stimulatory G protein G_s are up-regulated and then subsequently down-regulated before the onset of labor (1, 2), whereas levels of expression of the myometrial gap junction protein connexin-43 (3, 4, 5, 6) and the inducible cyclooxygenase-2 (COX-2) isoform (7) are increased severalfold before and during parturition in humans and lower mammals, respectively.

In the human, most observations on the expression and function of myometrial genes involved in controlling the activity of the uterus during pregnancy and at the onset of parturition have been performed on tissue from the lower uterine segment obtained at cesarean section. However, these studies may not reflect the molecular and biochemical events that occur in the upper regions of the uterus. Recent studies in the baboon indicate that the PG EP₂ and EP₃ receptors are differentially expressed within the uterus during gestation (8). In addition, oxytocin binding studies in human myometrium (9) have shown that the increase in oxytocin receptor numbers near term results in a gradient of expression, with the highest and lowest receptor concentrations found in the fundus and cervix, respectively. This differential expression of oxytocin receptors may be involved in directing the correct propagation of contractions from the fundus to the cervix during the course of labor. A similar fundus to cervix gradient has also been described for PG receptors in the nonpregnant human uterus (10). In contrast, Moonen et al. (11) have reported a cervix to fundus gradient in the expression of myometrial PGH synthase (i.e. COX-1 and -2) in microsomal preparations from a 34-week cesarean hysterectomy specimen. These reports raise the possibility that other proteins implicated in the switch from myometrial quiescence to activation may also be spatially regulated. The purpose of the present investigation was, therefore, to determine whether this was the case by examining the relative levels of expression of connexin-43, COX-1 (the constitutive isoform). COX-2 (the inducible isoform), and G_s proteins using specific antibodies with Western immunodetection in paired samples of myometrium taken from the lower and upper segments of uteri in laboring and nonlaboring women.

	Materials and Methods

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Materials

All electrophoretic reagents were of the highest grade available and were obtained from Bio-Rad Laboratories, Inc. (Richmond, CA). Primary antibodies for the study were connexin-43 monoclonal antibody MAB3068 from Chemicon (UK), COX-1 polyclonal antibody sc-1752AC from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA), COX-2 monoclonal antibody C22420 from Transduction Laboratories, Inc. (Lexington, KY), and G_s antibody RM/1 and Gß antibody SW/1 from New England Nuclear Corp. (Boston, MA). Secondary antibodies were goat antirabbit IgG/goat antimouse IgG linked to horseradish peroxidase from DAKO Corp. (UK) and antigoat IgG horseradish peroxidase-linked antibody from Santa Cruz Biotechnology, Inc. The enhanced chemiluminesence assay system was obtained from Amersham International (Aylesbury, UK).

Selection of patients and tissue collection

Twenty-five women undergoing elective lower segment cesarean section at 38–39 weeks gestation were recruited from the antenatal ward before surgery. The second group consisted of 25 women in spontaneous labor at term who required emergency cesarean section for fetal distress or failure to progress. Spontaneous labor was defined as regular uterine contractions and cervical dilatation of more than 3 cm on admission. Augmentation of labor with oxytocin was not a reason for exclusion, provided the onset of labor had been spontaneous. Routine cesarean section was carried out under subarachnoid block or general anesthetic. After delivery of the infant, the placental site was confirmed manually, and the placenta was delivered. Five nonfundal, upper segment biopsies (100–250 mg) were taken from within the uterine cavity using laparoscopic biopsy forceps (Wolf) introduced through the lower segment incision. Biopsies were taken from the side opposite the placental bed. In addition, a 1- to 2-cm sample of myometrium was taken from the upper margin of the lower uterine segment incision using tissue forceps and scissors. Note that paired upper and lower segment tissue samples were taken from all women in each patient group. The myometrial samples were snap-frozen in liquid nitrogen and stored at -70 C. Written consent was obtained from all women, and ethics approval for the study was granted by the Newcastle and North Tyneside Health Authority ethics committee.

Preparation of myometrial homogenates and Western blot immunodetection of myometrial proteins

All procedures were carried out on ice. Samples were homogenized at a ratio of 1:10 in 25 mmol/L Tris base buffer, pH 7.6, containing 0.25 mol/L sucrose and 1 mmol/L ethylenediamine tetraacetate in the presence of a protease inhibitor cocktail from Sigma Chemical Co. (St. Louis, MO) that contained 4-(2-aminoethyl) benzenesulfonyl fluroride, trans-epoxysuccinyl-L-leucylamido (4-guanidino) butane (E-64), bestatin, leupeptin, aprotinin, and sodium ethylenediamine tetraacetate, used at a 1:10 dilution. Homogenates were then centrifuged at 1000 x g to remove tissue debris, and supernatants were stored at -70 C. Protein was assayed by the method of Bradford (12) with BSA as standard. Proteins (300 µg) from myometrial homogenates were solubilized in sample buffer, resolved on 12.5% polyacrylamide gels containing 0.0625% bis-acrylamide for 5–6 h at 40 mAmp, and then elecrotransferred onto nitrocellulose at 90 V for 2 h. Before antibody immunodetection, nitrocellulose blots were blocked for 60 min in 5% nonfat milk in phosphate buffered saline (PBS). The connexin-43 antibody was used at a 1:1000 dilution in the presence of 3% nonfat milk and 0.05% Tween-20 in PBS overnight at 4 C. Antibodies to COX-1 and COX-2 were used at a 1:2000 dilution in the presence of 5% nonfat milk and 0.05% Tween-20 in PBS overnight at 4 C. Antibodies to G_s and Gß were used at a 1:1000 dilution in PBS for 90 and 60 min, respectively, at room temperature. Primary antisera were removed, and blots were washed thoroughly with PBS. Blots were then incubated with goat antimouse IgG, antigoat IgG, or goat antirabbit IgG coupled to horseradish peroxidase at a 1:1000 dilution for 60 min at room temperature and washed with PBS. Recent studies have indicated that expression of the Gß subunits in lower segment myometrial samples taken from nonpregnant, pregnant nonlaboring, and spontaneous laboring women is the same (1, 13). Therefore, all membranes were reprobed with the Gß antibody (SW/1) to double check that similar levels of myometrial smooth muscle protein were loaded in each lane, as all nitrocellulose membranes were previously stained with Ponceau S solution (Sigma Chemical Co., UK) and scanned before immunoblotting to monitor lane loading. In control experiments all antibodies were substituted with nonimmune serum from animals in which the antibodies were raised (data not shown). In all cases, immunodetected bands were specific. Data were obtained under conditions where a linear relationship existed between the amount of protein loaded and the intensity of the enhanced chemiluminescence signal from the immunoblots. The intensities of immunoreactive staining were measured using a scanning densitometer coupled to the Intelligent Quantifier software package from BioImage (Ann Arbor, MI). Data were compared using one-way ANOVA with the Bonferroni post test; P < 0.05 was considered significant. Results are expressed as the mean ± SEM.

	Results

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The Western blot images described in the figures below are representative of the results obtained from each of the specific antibodies used in this investigation. Quantification by scanning densitometry of connexin-43, COX-1, COX-2, G_s, and Gß proteins in all of the experiments are represented graphically; n is the number of myometrial samples analyzed from each tissue group. Immunoblotting with the specific connexin-43 monoclonal antibody MAB3068 detected major bands of 43 and 38 kDa, which have been described previously and represent different phosphorylated forms of this protein (6, 14, 15, 16). As in all of the experimental designs, large electrophoresis SDS-PAGE gels were used, and gels were regularly run for a further 30–40 min after the dye front had been removed so as to maximize protein separation, we also frequently observed a connexin-43 isoform with a molecular mass between 38–43 kDa, which may represent another phosphorylated isoform or result from proteolytic breakdown. Quantification of the most commonly identified 43- and 38-kDa myometrial connexin-43 proteins resulted in a significant increase in expression of this gap junction protein in upper segment myometrial samples compared with that in lower segment tissues taken at term (P < 0.05). This effect was amplified further during spontaneous labor (Fig. 1, a and b; P < 0.01). There was also a significant increase in connexin-43 expression when comparing laboring with nonlaboring myometria (lower and upper segments; P < 0.01). It should be noted that if all immunodetected connexin-43 protein bands were taken into consideration, the same changes in connexin-43 expression were still observed between the different myometrial tissues (data not shown).

View larger version (27K): [in this window] [in a new window]   Figure 1. Immunodetection of human myometrial connexin-43 gap junction protein in lower (LS) and upper (US) uterine segments in laboring (L) and nonlaboring (NL) term myometrium. a, Connexin-43 proteins were resolved by SDS-PAGE and subsequent Western blotting. The antibody MAB3068 was used at a 1:1000 dilution. b, Immunodetected bands were quantified by scanning densitometric analysis. Data are expressed as the mean ± SEM (n = 22 women). NL: US vs. LS, P < 0.05; L: US vs. LS, P < 0.01; NL vs. L (US and LS), P < 0.01.

View larger version (37K): [in this window] [in a new window]   Figure 2. Immunodetection of human myometrial COX-1 and -2 in lower (LS) and upper (US) uterine segments in laboring (L) and nonlaboring (NL) term myometrium. a, COX-1 and COX-2 proteins were resolved by SDS-PAGE and subsequent Western blotting. Antibodies sc-1752AC (COX-1) and C22420 (COX-2) were used at a 1:2000 dilution. b, COX-1 and COX-2 immunodetected bands were quantified by scanning densitometric analysis. Data are expressed as the mean ± SEM (n = 10). NL: US vs. LS, P < 0.05; L: US vs. LS, P < 0.05.

View larger version (37K): [in this window] [in a new window]   Figure 3. Immunodetection of human myometrial Gs and Gß GTP-binding protein subunits in lower (LS) and upper (US) uterine segments in laboring (L) and nonlaboring (NL) term myometrium. a, Gs and Gß proteins were resolved by SDS-PAGE and subsequent Western blotting. Antibodies RM/1 (Gs) and SW/1 (Gß) were used at a 1:1000 dilution. b, Gs and Gß proteins were quantified by scanning densitometric analysis. Data are expressed as the mean ± SEM. Gs nonlaboring, n = 12; laboring, n = 15; Gß, n = 22. Gs, LS: NL vs. L, P < 0.05; US: NL vs. L, P < 0.05.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
In this investigation, we have used a novel sampling technique to collect upper segment myometrium from laboring and nonlaboring women, allowing comparisons to be made with myometrium taken from the cesarean section incision from the same women. Our findings indicate that certain proteins, implicated in the switch from quiescence to uterine activity, show major expression differences not only during labor but also between upper and lower segment myometria.

Our results confirm the report by Chow and Lye (6) indicating that expression of connexin-43 protein, which is involved in gap junction formation in both rats (22, 23, 24) and humans (25) and thus the conductance of electrical activity via cell-cell communication within the uterus, is increased in the human myometrium toward term and with the onset of parturition. However, the data presented here strongly suggests that myometrial connexin-43 protein expression is much greater in the upper segment compared with the lower segment, and this difference is much more pronounced during parturition. The differential expression of connexin-43 in conjunction with the topographical distribution of oxytocin receptors (9) may thus underlie the propagation of uterine contractions from the fundus to the cervix during delivery of the fetus.

Both COX-1 and COX-2 have been shown to be responsible for the synthesis of prostacyclin, PGE₂, and PGF₂ (17), which are all involved in regulating the activity of the uterus during pregnancy and parturition. Prostacyclins are known to act through the myometrial IP receptor increasing cAMP levels, resulting in uterine relaxation. Similarly, PGE₂ can cause uterine relaxation via interaction with the EP₂ receptor, but may also cause contraction via interaction with EP₁ and EP₃ receptor subtypes (26). In contrast, PGF₂ acts mainly through the FP receptor, resulting in calcium mobilization and activation of the contractile machinery. Previous reports of the expression of the cyclooxygenases in the myometrium are conflicting. For example, the expression of COX-1 and COX-2 is increased in the rat (7), but reduced in the human (17), at the onset of labor compared to that in the nonlaboring state. In contrast to these reports we have found no change in the expression of either COX-1 or COX-2 after the onset of parturition. However, our results concur with those of Moonen et al. (11), indicating much higher concentrations of these enzymes in the lower compared with the upper segment of the uterus. It may be that these high concentrations of COX-1 and COX-2 increase prostacyclin/PGE₂ production, which increases the collagenolytic activity of the cervical tissue, resulting in cervical ripening before the onset of labor. Thereafter, once labor begins, increased local production of prostacyclin/PGE₂ may result in a greater relaxation of the lower uterine segment, thus facilitating cervical dilatation, as previously suggested by Zuo et al. (17). Similarly, Stevens et al. have shown that the myometrial CRH receptor subtype 1 (CRH-R1) is also differentially expressed within the human uterus during gestation and parturition, with the highest levels expressed in the lower compared to the upper uterine segment (27), which may also facilitate relaxation of the lower uterine segment during labor, as this hormone acts through the cAMP signaling pathway.

We also provide evidence that the adenylyl stimulatory G protein G_s is expressed uniformly in upper and lower myometrial segments of the uterus during pregnancy, and this may facilitate uterine relaxation. At the onset of labor, G_s is down-regulated in both uterine regions, which may result in a uniform decrease in cAMP production, as previously described (1).

Ambrus et al. (28) have shown that hCG can directly decrease connexin-43 messenger ribonucleic acid, protein, and morphological gap junctions in primary cultures of human myometrial cells and that this effect is mediated by protein kinase A signaling. Therefore, the increase in connexin-43 expression at term may be linked to the decrease in cAMP formation as a consequence of down-regulation of both G_s proteins (1) and hCG (2) receptors before the onset of parturition. This sequence of events may be responsible for the switch from uterine quiescence to activation. In addition, there is evidence that hCG can up-regulate the expression of COX-1 in human fetal membranes (29), and a similar mechanism may regulate the expression of COX-1 and COX-2 in the myometrium.

In conclusion, the present study suggests that the expression of several genes that are important in regulating the activity of the uterus during pregnancy and labor are not only temporally but also spatially regulated. Our results emphasize the importance of studying myometrium from both the upper and lower segments of the uterus, as changes occurring in one area may not necessarily give a true reflection of what is happening in the organ as a whole. The elucidation of the molecular mechanism that controls the differential expression of these proteins may, in the future, lead to better therapies in the treatment of preterm delivery and other labor-associated disorders.

	Footnotes

 
¹ This work was supported by the Wellcome Trust grant 053563, Action Research grant S/P/3232, and Tommy’s Campaign grant No 271.

Received December 3, 1998.

Revised January 13, 1999.

Accepted January 21, 1999.

	References

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