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Canadian Institutes of Health Research in Human Development, Child and Youth Health (D.G., F.A.P., A.C.H., S.J.L., J.R.G.C.), Departments of Physiology & Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada M5S 1A8; and Samuel Lunenfeld Research Institute, Mount Sinai Hospital (S.J.L.), College of Pharmacy (H.H.T.), University of Kentucky, Lexington, Kentucky 40536-0001
Address all correspondence and requests for reprints to: Ms. Diana Giannoulias, 1 King’s College Circle, Medical Sciences Building, Room 3344, Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Abstract
Prostaglandins (PGs) play a key role in the onset of labor in many species and regulate uterine contractility and cervical dilatation. Therefore, the regulation of prostaglandin output by PG synthesizing (PGHS-I and PGHS-II) and metabolizing (PGDH) enzymes in the human myometrium may determine uterine activity patterns in human labor both at preterm and at term. We hypothesized that expression of PGHS isozymes and PGDH in myometrium from women at preterm and term labor would change to favor increased uterotonin (PG) production. Myometrial samples were obtained from the lower uterine segment during cesarean section deliveries from women presenting in preterm, no labor; preterm, labor; term, no labor; term, labor. Immunoreactive (ir-) PGHS and PGDH protein was localized using immunohistochemistry, and changes in protein levels were determined by Western blotting. Ir-PGHS-I and PGHS-II proteins were localized only to myocytes. Ir-PGDH was localized to myocytes in all samples of myometrium examined, but using dual immunofluorescence and immunohistochemistry, ir-PGDH was also detected in cells of the connective tissue. Levels of ir-PGHS-I and PGHS-II protein were not significantly different between no labor and labor tissues, either at preterm or at term. There was no significant effect of gestational age on levels of PGDH, PGHS-I, and PGHS-II protein, but there was a significant decrease in ir-PGDH protein levels in myometrium with labor both at preterm and at term. In addition, there was a decrease in PGDH activity in myometrium from women in labor, both at preterm and at term. Therefore, we conclude that PGDH, PGHS-I, and PGHS-II protein localize within the myocytes of the human pregnant myometrium. A decrease in PGDH protein and activity occurs in association with active labor and may contribute to the amount of bioactive PGs available to act within the human pregnant myometrium at that time.
PRETERM LABOR OCCURS in 5–10% of pregnancies, accounting for nearly 70% of early neonatal morbidity and mortality (1). Prostaglandins (PGs) act as potent uterotonins at the time of labor, affecting myometrial contractility and cervical dilatation (2). Primary PGs, PGE2, and PGF2
are formed from arachidonic acid through the peroxidase and cyclooxygenase actions of prostaglandin H synthase (PGHS) (3). Two known isoforms of PGHS have been described. PGHS-I is considered the constitutive form of the enzyme, whereas PGHS-II is the inducible form of the enzyme (4), up-regulated in response to proinflammatory cytokines, growth factors, and mitogens (5). PGs are inactivated by an NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH), which catalyzes the initial conversion of PGE2 and PGF2 to their biologically inactive 15-keto derivatives (6). Changes in levels of PGDH, PGHS-I, and PGHS-II, therefore play important roles in regulating the synthesis, metabolism, and availability of primary PGs that are implicated in the labor process (7).
In human pregnancy, the amnion and chorion are major sites of PG synthesis and metabolism (8). PGHS-I and PGHS-II are expressed in the amnion, chorion, and decidua, whereas PGDH mRNA and protein have been localized mainly in the chorion trophoblast cells (9, 10). Thus, the chorion has been described as a protective barrier preventing the transfer of PGs synthesized within the amnion and chorion to the underlying decidua and myometrium (10, 11). PGDH activity decreases in the chorion of some patients in idiopathic preterm labor, lessening the protective barrier and allowing bioactive PGs to reach the myometrium and stimulate contractility (12).
There is little information, however, concerning potential changes in PGHS and PGDH expression in the myometrium itself at preterm labor. Previous studies have reported that PGHS-II in myometrium either increases (13), decreases (14), or remains the same (15, 16) at term labor. We reasoned that increased PG output could be altered by diminished metabolism, as well as increased synthesis, depending on the levels and cellular localization of these enzymes. Therefore, we obtained samples of lower segment human myometrium to determine localization and levels of PGHS and PGDH protein in association with labor, either at term or preterm.
Materials and Methods
Tissue collection
Patient consent and ethical approval was obtained before the onset of the study and tissue collection, according to the regulations of Mount Sinai Hospital (Toronto, Canada) and the University of Toronto. Tissues were collected from the upper edge of the lower uterine segment during cesarean section deliveries and either snap frozen in liquid nitrogen for protein extraction or slow frozen for use in immunohistochemistry. Myometrial tissue samples were then separated into four groups, preterm (28–36 wk), not in labor (n = 8) and labor (n = 4); term (38–40 wk), not in labor (n = 8) and labor (n = 6). Labor was defined as the presence of regular uterine contractions resulting in cervical dilatation. Cesarean sections were either scheduled (nonlaboring patients) or performed because of fetal or maternal complications (laboring patients). Indications for cesarean section were: preterm no labor (fetal anomalies n = 3, maternal condition n = 3, triplets n = 2); preterm labor (fetal anomalies n = 1, breech n = 3); term no labor (previous cesarean section n = 5, breech n = 3); term labor (fetal distress n = 3, failure to progess n = 3). None of the patients in this study had received prostaglandins or oxytocin.
Immunohistochemistry
PGHS-I and PGHS-II protein were localized with specific polyclonal rabbit antihuman antibodies (PG-19 and PG 27B, Oxford Biomedical Research, Oxford, MI) and diluted in antibody dilution buffer at a 1:200 dilution. The PGDH antibody was a polyclonal antibody, raised in rabbits against purified type I placental PGDH, and used at a 1:3000 dilution (17). A monoclonal mouse anti-smooth muscle- actin antibody (A2547, Sigma, St. Louis, MO) diluted at 1:3000 was used to identify smooth muscle. Antibodies were diluted in 1% BSA in PBS: 150 mM NaCl, 10 mM Na2HPO4, 1.5 mM NaH2PO4 (pH 7.5). Antibody binding was visualized using the Vectastain avidin-biotin peroxidase complex kit (Vector Laboratories, Inc., Burlingame, CA) using 3,31-diaminobenzidine (Sigma) as the chromagen. Myometrial tissues were cut (12-µm sections) and fixed with 4% paraformaldehyde. Tissues were then rehydrated with increasing dilutions of ethanol (100%, 90%, 70%, 50%) ending with two washes of PBS. Endogenous peroxidase activity was removed by pretreatment with 0.3% hydrogen peroxide in PBS. The tissues were then incubated with normal goat or horse immune serum, depending upon the primary antibody used, as a blocking agent to eliminate nonspecific binding. Next the primary antibody was applied to the tissues and incubated at 4 C for 18–24 h. Following incubation, tissues were washed in PBS, incubated with biotinylated secondary antibody for 2 h, washed again in PBS, and incubated with an avidin-biotin peroxidase complex for 2 h. After a final washing with PBS, the immunoreactive proteins were visualized following the addition of diaminobenzidine powder (Sigma) for 3 min. The tissues were counterstained with Carazzi’s hematoxylin, dehydrated in ethanol (50%, 70%, 90%, 100%) and then placed in xylene for three washes. Negative controls were treated in an identical manner, except that the PGDH, PGHS-I, and PGHS-II antibodies were preabsorbed with their antigens overnight at 4 C, and applied to tissue sections.
Dual immunofluorescence
Tissue sections were rehydrated in serial dilutions of alcohol (100%, 90%, 70%, 50%) and washed in PBS. Nonspecific binding of antibodies was blocked with 1% BSA in PBS for 2 h at room temperature. The samples were then incubated with the same primary antibodies as above; anti-smooth muscle -actin (1:3000) with either rabbit antihuman PGHS-II (1:200) or rabbit antihuman PGDH (1:3000), and placed in a 1% BSA solution containing 0.3% Triton-X 100. Tissue sections were incubated overnight (18–24 h) with the primary antibodies at 4 C. Following the incubation period, the sections were washed three times in 0.1 M PBS. The secondary antibodies were added, and incubated at 37C for 45 min. The secondary antibodies used were a fluorescein conjugated sheep antimouse IgG used at 1:50 dilution (Amersham Pharmacia Biotech, Baie d’Urfé, Québec, Canada) and a CY3 conjugated sheep antirabbit IgG used at a 1:1000 dilution in a 1% BSA solution. Samples were washed again in PBS and then dehydrated in serial dilutions of alcohol (50%, 70%, 90%, 100%). Antifading reagent (p-phenylendiamine, 1 mg/ml, 50% glycerol, 50% PBS) was added to the tissue sections, and coverslips applied before analysis.
Microscope analysis
Tissue sections were analyzed under a fluorescent Optiphot-2 microscope (Nikon) using a green filter to visualize FITC and a red filter to visualize CY3. A Sensicam 12 bit cooled monochrome imaging camera (Cooke Inc., Auburn Hills, MI) was used to take a digital photograph of the section using Sensicontrol 4.02 software (Cooke Inc., Auburn Hills, MI), and this was visualized on a computer. The highlights in the monochromatic images indicate brighter fluorescence. The images taken from the camera were then exported into Coreldraw (Corel, Eastman Kodak Co., Rochester, NY), and computer-generated color images were produced. These images were superimposed to obtain the localization patterns of PGHS-II or PGDH with -actin. If the two images completely superimpose, this indicates that the enzyme of interest is present in the same cell type expressing -actin.
Western blot analysis
Myometrial samples were homogenized on ice with Radioimmunoprecipitation buffer lysis buffer (50 mM Tris HCl, pH 7.5; 150 mM NaCl; 1% Triton-X 100; 1% sodium deoxycholate; 0.1% SDS), Mini EDTA-free protease inhibitor (Roche Molecular Biochemicals, Laval, Québec, Canada), and sodium orthovanadate (Sigma). Homogenates were centrifuged at 1,000 x g to remove tissue debris, and supernatants were transferred to Eppendorf tubes and stored at -80 C. Protein was assayed using the Bradford protein assay (18) using BSA standards. Proteins (100 µg) from myometrial homogenates were solubilized in Laemelli sample buffer (10% SDS, 0.5 M Tris, glycerol, 0.2% Bromophenol blue; Bio-Rad Laboratories, Inc., Hercules, CA), boiled at 55C for 15 min, and resolved onto 11% Bis-acrylamide gels at 100 V for 2 h. They were then transferred onto a nitrocellulose membrane (Bio-Rad Laboratories, Inc.) at 110 V for 2 h. Proteins were visualized with Ponceau S solution (Sigma) and scanned before immunoblotting to ensure equal lane loading. Nitrocellulose blots were blocked with 5% nonfat milk (Nestle, Glendale, CA) in PBS and 0.1% Tween-20 (Sigma) at 4 C for 18–24 h. The PGHS-I and PGHS-II antibodies (1:500 dilution) and the PGDH antibody (1:3000 dilution) were mixed with 5% nonfat milk solution and 0.1% Tween-20 and added for 1 h at 22 C. Primary antibodies were then removed. The blots were washed with PBS and 0.1% Tween-20, and then incubated with either antirabbit IgG or antigoat IgG coupled to horseradish peroxidase (Amersham Pharmacia Biotech, Baie d’Urfé) at a 1:2000 dilution for 1 h at room temperature and then washed with PBS and 0.1% Tween. ECL detection reagents (Amersham Pharmacia Biotech) were added to the membranes for 1 min, whereupon the membranes were exposed to X-OMAT blue film (Kodak Scientific Imaging Products, Rochester, NY). The intensities of immunoreactive bands were measured using a scanning densitometer coupled to MCID software (Imaging Research, Inc., St. Catharines, Ontario, Canada). Protein bands were digitized and the mean pixel density for each band was analyzed to obtain relative optical density units for each protein. Previous studies indicate that the expression of Gß-subunits does not change in lower segment myometrial samples taken from pregnant nonlaboring and laboring women (19). Therefore, Gß was used as an internal control to ensure that similar levels of myometrial smooth muscle protein were loaded in each lane. The PGDH blots were stripped (0.1 M glycine, pH 2.7, Sigma) and reprobed with the Gß antibody (Santa Cruz Biotechnologies, Santa Cruz, CA). The PGHS-I and PGHS-II blots were cut in half, and the upper half of the blot was incubated with either the PGHS-I or PGHS-II antibody and the bottom half of the blot was incubated with the Gß antibody. The Gß antibody detected a 40-kDa protein with no change associated during pregnancy or labor at term or preterm. To compare measurements between blots prepared at different times, an aliquot from a control term placenta was also included on each blot.
PGDH activity
The activity of type I NAD+-dependent PGDH enzyme was determined using a modification of the enzyme assay described previously (20). Briefly, a portion of frozen myometrium was weighed and placed in metabolism buffer (0.1 M PBS, containing 20% (vol/vol) glycerol and 2 mM dithiothreitol [Sigma]; 50 mg tissue ml-1 buffer; 4 C). Tissues were homogenized and centrifuged at 10,000 x g for 2 min. The supernatant of the homogenate was diluted 1:20 with metabolism buffer and incubated with 1 mmol NAD+ and 25 ng PGF2 (Sigma) substrate in excess for 15 min at 37 C. The reaction was stopped by placing the samples on ice. PGDH activity was determined by using RIA to measure the concentration of 13,14-dihydro-15-keto PGF2 as described previously (21).
Statistical analysis
Results from western blotting are presented as the mean ± SEM and analyzed using a two-way ANOVA. Statistical significance was set at P 
0.05. t test was used if the two-way ANOVA indicated a significant main effect. Calculations were performed using Sigma Stat (Jandel Scientific Software, San Rafael, CA). PGDH activity was analyzed using a t test. Groups were checked for normality. If this condition was not met, the data were analyzed by Mann-Whitney Rank sum test ( = 0.05).
Results
Positive cytoplasmic staining for ir-PGHS-I, PGHS-II, and PGDH protein was observed in myometrial smooth muscle cells from pregnant women in all 4 groups (Fig. 1
, A, C, and E). The immunostaining was abolished when immune serum was substituted for the primary antibody (Fig. 1, B, D, and F). The localization pattern was confirmed with dual immunofluorescence, showing that PGHS-II and -actin were colocalized in the myocytes; PGHS-II was not detected in stromal tissue (Fig. 2, B and C). PGDH also colocalized with -actin in myocytes; in addition, it was present in connective tissue cells that did not stain with -actin (Fig. 2, E and F).
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). There was no significant effect of gestational age on PGHS-II expression (Fig. 3B), and there was no significant change in PGHS-II protein levels with labor at preterm or at term. PGHS-I (69 kDa protein) did not change with gestational age nor was there any significant effect of labor at preterm or term (data not shown). Immunodetection of PGDH revealed three bands at 25, 50, and 56 kDa representing the monomeric and dimeric forms of the enzyme, respectively (6) (Fig. 4A). These bands were eliminated upon preabsorption with the primary antibody. The 25-kDa band is considered to represent bioactive PGDH (6, 22, 23, 24); there was no significant effect of gestational age (preterm no labor vs. term no labor) on levels of this protein. However, there was a significant decrease in 25 kDa ir-PGDH protein levels at preterm labor compared with preterm no labor, and there was also a significant decrease in ir-PGDH protein levels in myometrium from patients in labor at term compared with tissues from term, no labor, patients (Fig. 4B). There were no significant changes in the ratio of either 50-kDa or 56-kDa isoforms relative to Gß with gestational age or with the process of labor (both P > 0.05, data not shown). Mean PGDH activity was lower in samples of myometrium from patients in labor, both at term and preterm (Fig. 5, inset), and overall PGDH activity in myometrium from laboring patients was significantly lower than in tissue from patients not in labor (P = 0.05; Fig. 5).
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This study has revealed that ir-PGDH, PGHS-I, and PGHS-II protein are localized to myocytes from term and preterm myometrium. Ir-PGDH was also present in cells of the connective tissue. Western blotting analyses indicated that ir-PGHS-I and PGHS-II protein levels did not change significantly with labor or gestational age. However, there was a decrease in ir-PGDH protein and PGDH activity at preterm and term labor, consistent with the possibility that reduced metabolism of PGs could contribute to an increase in PG levels in the lower uterine segment.
Western blot analysis revealed bands of ir-PGHS-I and PGHS-II with molecular weights of 69 and 72 kDa, as described previously (15). The lack of change in ir-PGHS-I and PGHS-II protein levels with labor at preterm and term is in agreement with the results of Sparey et al. (15), who reported that PGHS-I and PGHS-II protein levels in the upper and lower uterine segment were unaffected by the onset of parturition (15). However, myometrial PGHS-I and PGHS-II proteins appear to be expressed at much greater levels in the lower compared with the upper uterine segment (15). Our results also agree with those of Moore et al. (16), who found no significant change in PGHS-I and PGHS-II mRNA in the lower uterine segment with advancing gestational age or labor. In contrast, Zuo et al. (14) reported that PGHS-II expression was lower with labor compared with not in labor at both preterm and term, although PGHS-I expression did not change as in the present study. Slater et al. (13) also reported no significant change in PGHS-I mRNA and protein with labor, in agreement with the present results. However, these investigators found a significant up-regulation in myometrial PGHS-II mRNA with advancing gestational age (13). More recently, Erkinheimo et al. (25) found a 15-fold elevation in PGHS-II mRNA in lower segment myometrium at the onset of labor. It is possible that these differences may reflect the sites of sampling of the myometrium, the medication such as oxytocin or PGs given to these patients or variation in the proximity to labor of the patients classified as not in labor at both gestational ages. The study by Zuo et al. (1994) used qualitative scoring of tissue sections that could explain the difference in their results when compared with the present study and the studies of Sparey and Moore (15, 16).
Western blot analysis of ir-PGDH in the pregnant myometrium revealed a protein band of 25 kDa, similar to the reported molecular weight of PGDH in rabbit lung, pig, and rabbit kidney (6, 22, 23) and bands of 55–56 kDa, believed to represent dimeric forms of the protein (23). It is possible that the 50- to 56-kDa forms represent dimeric forms of the enzyme another isoenzyme (26) or glycosylated forms of the protein. We have shown a decrease in the 25-kDa protein band at the time of labor in both preterm and term groups. Although, we found no change in the 50- and 56-kDa bands with labor at both time points, we did observe an overall decrease in PGDH activity with labor compared with patients not in labor. This is consistent with reports that the 25-kDa band is the active form of PGDH (6, 22, 23, 24). The localization pattern of PGDH has not been previously described. Dual immunofluorescence and immunohistochemistry indicated that ir-PGDH is present in myocytes of myometrium from pregnant women and was also present in cells of the intervening connective tissue. Previous studies have examined the localization and activity of PGDH in human fetal membranes and placenta. Specifically, ir-PGDH was not detected in the amnion epithelial and subepithelial layers but abundantly localized to the chorionic trophoblast layer (27). In placenta, PGDH was present in the syncytiotrophoblast and intermediate trophoblasts but absent from cytotrophoblast cells (17, 27). We have reported elsewhere that the distribution of PGDH in the cervix is similar to that reported here for the myometrium (28). In the cervix, altered PG output locally may contribute to remodeling in preparation for cervical dilatation at the time of labor (28).
We found that PGDH protein levels in myometrium decreased significantly during labor at preterm and at term. Keirse et al. (1975), measured the activity of PGDH in the placenta, fetal membranes, and myometrium and found the highest activity was present in the chorion and placenta, followed by the myometrium and decidua (29). However, changes in PGDH levels and activity in myometrium and decidua at the time of labor were not reported (29). In the present study, we found that PGDH activity decreased at both term and preterm labor, consistent with the decline in ir-PGDH protein. Recently Wu et al. (30) reported that there was no change in PGDH mRNA in the lower myometrial segment of the pregnant baboon during spontaneous labor, but there was a decrease in PGDH mRNA in the fundus (30). Further studies are required to determine regional differences in PGDH expression between different areas of the human uterus and relative expression and activity of PGHS-I, PGHS-II, and PGDH. In addition, studies are needed to determine whether the decrease in PGDH protein and activity results mainly from decreased expression, or increased turnover of the protein in the face of increased PG synthesis. However, the decrease in myometrial PGDH protein reported here in the lower segment is consistent with the pattern of reduced PGDH mRNA reported in cervical tissue from women in labor at term or preterm (28). There is little information on uterine PGDH in nonprimate species. In pregnant sheep, there is a fall in myometrial PGDH with labor, suggesting some consistency in this observation across different species (31). PGDH is the major initial metabolizing enzyme of PGs. Thus, although we found no change in the prostaglandin synthesis enzymes, a decrease in metabolism may lead to an increase in the level of bioactive PGs that would be available to act within the lower segment of the human myometrium. These results strongly suggest an important role for the modulation of PGDH during human labor. We have suggested elsewhere (32) that the relative importance of PG synthesis and metabolism in the fetal membranes and myometrium might differ between labor at term, and in different circumstances of preterm labor. It seems more likely that PGs from fetal membranes would affect the myometrium if chorionic PGDH was reduced or absent, whereas at normal term, those PGs influencing myometrial activity would be generated in the myometrium itself, particularly if the chorion PGDH barrier was undisturbed.
Some studies have suggested that at the time of human labor, the lower uterine segment remains relatively passive and dilates to allow the passage of the fetus, whereas the upper fundal segment has to generate the force necessary to expel the fetus (33). In support of this hypothesis, it has been demonstrated previously that the lower uterine segment has a more pronounced relaxant response to EP2 and IP receptor activation, by PGE2 and PGI2, respectively (34). While PGE2 inhibited contraction of the lower segment myometrium during spontaneous labor, PGF2 had no effect (33). However, PGF2 stimulated the upper segment to contract (33). The decrease in PGDH in the lower uterine segment may alter the availability of bioactive PGE2 relative to PGF2. PGDH appears to have a higher affinity for PGE2 as substrate then PGF2 (6, 23). Therefore, the decrease in PGDH during labor would be expected to have a greater impact on PGE2 metabolism, leading to higher relative PGE2 levels. Because activation of the EP2 receptor (promoting relaxation) occurs at higher PGE2 levels, and activation of EP3 (contractile) receptors occurs at lower PGE2 levels (33), increased PGE2 levels could promote relaxation of the lower segment myometrium. Future work will need to make a comparison of PGDH, PGHS-I and PGHS-II expression and activity in myometrium from the upper and lower segment of the uterus to understand better the potential for differential regulation of uterine contractions and the role of PG synthesizing and metabolizing enzymes in the labor process.
Acknowledgments
We thank Cristine Botsford and Lindsay McWhirter (Mount Sinai Hospital, Toronto, Ontario, Canada) for their assistance in collecting tissues for these studies, Nohjin Kee, for helping with the analysis of the dual immunofluorescence labeling, and a special thanks to Dr. M. Wiley for his helpful comments.
Footnotes
This work was supported by the Canadian Institutes of Health Research in Human Development, Child and Youth Health (MOP 42378).
Abbreviations: ir, Immunoreactive; PG, prostaglandin; PGDH, PG metabolizing enzymes; PGHS-I and -II, PG synthesizing enzymes.
Received August 17, 2001.
Accepted November 30, 2001.
References
proteins in the upper and lower segments of the human uterus during pregnancy and labor. J Clin Endocrinol Metab 84:1705–1710s in human myometrium in term, and preterm labor: a mechanism for parturition. J Clin Endocrinol Metab 79:1835–1839[Abstract]
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