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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 1 113-117
Copyright © 1997 by The Endocrine Society

Reproductive Endocrinology

Epidermal Growth Factor Receptors in Uteroplacental Tissues in Term Pregnancy before and after the Onset of Labor

Antonio R. Gargiulo, Firyal S. Khan-Dawood and M. Yusoff Dawood

Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Texas Medical School, Houston, Texas 77030

Address all correspondence and requests for reprints to: M. Yusoff Dawood, M.D., Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Texas Medical School, 6431 Fannin, Suite 3.204, Houston, Texas 77030. E-mail: ydawood{at}obg.med.uth.tmc.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Using saturation binding assays and Scatchard analyses, we determined the concentrations and binding affinities of epidermal growth factor (EGF) receptors in human myometrium (n = 13) and decidua (n = 10) before and during labor and in placenta (n = 15), chorion (n = 17), and amnion (n = 17) before labor, during labor, and after vaginal delivery. Each tissue was individually assayed. In myometrium and chorion, EGF receptors increased significantly from 5.6 ± 0.8 and 13.5 ± 1.7 fmol/mg protein (mean ± SEM) before labor to 11.1 ± 2.8 and 26.7 ± 3.0 fmol/mg protein, respectively, after the onset of labor (P < 0.05). In amnion, EGF receptors increased from 12.8 ± 2.7 fmol/mg protein before labor to 33.0 ± 2.3 fmol/mg protein during labor, but decreased significantly (5.9 ± 1.2 fmol/mg protein) with vaginal delivery (P < 0.05). Decidual and placental concentrations of EGF receptors did not change significantly with labor. The binding affinity of EGF receptors in all tissues studied did not change significantly with labor, as reflected by their respective association and dissociation constants. Up-regulation of EGF receptors in myometrium, chorion, and amnion with spontaneous labor may enhance stimulation of prostanoid production and stimulate uterine activity.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
EPIDERMAL growth factor (EGF) is an autocrine/paracrine modulator of cell growth, differentiation, and function in many tissues of several mammalian species (1). The specific receptor for EGF is a 170-kDa polypeptide with three major domains: a ligand-binding domain, a transmembrane domain, and a tyrosine kinase domain (2). The tyrosine kinase activity of this receptor is responsible for the downstream activation of other intracellular enzyme pathways that account for long term as well as short term responses to EGF (3, 4). In the rodent, physiological concentrations of EGF induce contractions of estrogen-primed uterine smooth muscle in vitro, with a rapid onset of rhythmic contractions and an increase in basal tone (5). These EGF-induced uterine contractions appear to involve activation of both the cyclooxygenase and lipoxygenase pathways, resulting in local production of specific eicosanoids, which stimulate intracellular influx of free calcium and, consequently, smooth muscle contractions (6).

In the nonpregnant human myometrium, EGF and its receptors are present (7, 8, 9, 10, 11) and their respective genes are also expressed in normal cultured myometrium (12) and leiomyoma (13, 14, 15, 16). Although EGF can stimulate uterine smooth muscle cell proliferation and tritiated thymidine uptake in vitro (10, 13, 17), the roles of EGF and its receptors in the human myometrium are largely unknown, and to date, their presence during pregnancy has not been described. In contrast, EGF and its receptors are present in human decidua, placenta, and fetal membranes (18, 19, 20, 21, 22, 23, 24, 25, 26, 27). Present throughout the menstrual cycle, EGF immunoreactivity in human endometrium is increased during the secretory phase and in gestational decidua (21). Messenger ribonucleic acid encoding for EGF is detectable in human endometrium and decidua (22), whereas the gene for EGF is expressed in the process of decidualization (26). EGF itself can induce decidualization of human endometrial cell cultures in the presence of progesterone (28). Human decidua, placenta, chorion, and amnion have specific binding sites for EGF (18).

Through its receptors, EGF is able to stimulate PG production in human decidua, amnion, and chorion (29, 30, 31). Amniotic fluid with its high levels of EGF (picomole range) near term (32) may locally provide the peptide. Therefore, an increase in either EGF itself and/or its receptor activity may stimulate eicosanoid production and uterine contractions. Hypothesizing that EGF receptors in human myometrium, decidua, placenta, and fetal membranes may be up-regulated with labor, we measured and compared the concentrations and binding characteristics of EGF receptors in these tissues before labor, during the active phase of labor, and after vaginal delivery.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Reagents

Receptor grade mouse EGF was obtained from Collaborative Research (Lexington, MA). 125I-Labeled human recombinant EGF ([125I]hEGF) with a specific activity of more than 900 Ci/mmol was purchased from Amersham (Arlington Heights, IL).

Patients and tissues

The study was approved by the committee for the protection of human subjects at the University of Texas Health Science Center (Houston, TX), and patients on whom myometrial biopsies were performed gave written informed consent. All patients were at 37 completed weeks to 41 weeks gestation and free of medical or surgical complications. The mean maternal age, parity, gestational age, and infant birth weight were not significantly different among the three study groups.

Myometrial biopsies were obtained from 13 women undergoing cesarean birth under regional anesthesia, 8 at elective cesarean sections (before the onset of labor) because of previous cesarean births or breech presentation, and 5 during labor (cervix dilated 4 cm or more). Oxytocin was used in 3 of 5 patients in labor (2 in the cesarean section group and 1 in the vaginal delivery group); no tocolytics or PG derivatives were used in any of them. After delivery of the placenta, a small strip of uterine muscle (3–4 g) was excised from the upper edge of the low cervical transverse uterine incision. Immediately cleaned, the specimen was dissected to obtain myometrium. Uterine decidua was taken at cesarean section from 10 patients (6 before labor and 4 during the active phase) by carefully scraping the decidua vera from the uterine cavity with a large sharp curette after the placenta and all membranes were delivered and removed. Seventeen amnion (7 before labor, 5 during the active phase of labor, and 5 after vaginal delivery) and 17 chorion (7 before labor, 5 during the active phase of labor, and 5 after vaginal delivery) were collected at cesarean or unassisted vaginal deliveries. After scraping the maternal surface of the chorion and washing it with normal saline to remove any decidual cells, the fetal membranes were identified and separated by teasing and sharp dissection. Fifteen placental specimens were obtained (5 before labor, 5 during the active phase, and 5 after vaginal delivery) by excising the central portion of a noncalcified cotyledon at delivery of the placenta. All specimens were rinsed with chilled physiological saline to remove any blood and other contaminating cells, carefully blotted to get rid of excess fluid, and immediately snap-frozen in liquid nitrogen to be transported to the laboratory and subsequently stored at -80 C until analysis.

Receptor preparation

Tissue samples were individually processed to obtain plasma cell membranes (33). The tissues were thawed and kept at -4 C for all subsequent processing to prepare the plasma membrane fraction. One gram of tissue was thoroughly rinsed with chilled physiological saline solution to wash off any residual blood, sliced into small pieces, and then minced. The minced tissue was homogenized in 10 mmol/L Tris-HCl buffer, pH 7.0, containing 250 mmol/L sucrose and 1 mmol/L CaCl2 using a tissue homogenizer as previously described (33). The homogenate was centrifuged at 800 x g at 4 C for 15 min. The supernatant, containing the cellular fractions, was removed and ultracentrifuged at 100,000 x g at 4 C for 60 min. After ultracentrifugation, the pellet containing the plasma membrane fraction was resuspended in incubation buffer containing 10 mmol/L Tris-HCl (pH 7.0), 5 mmol/L CaCl2, 75 mmol/L NaCl, and 0.5% BSA. The protein concentration in the plasma cell membrane preparation was determined by the method of Lowry et al. (34) using BSA as the standard. The volume of the plasma membrane preparation was adjusted to give the necessary final concentration for the receptor binding studies as described below.

Receptor binding studies

Mouse EGF was used as the standard. Aliquots of the plasma membrane preparation from the myometrium, decidua, placenta, chorion, and amnion, containing 250 µg protein, were incubated with [125I]hEGF, in the presence (50 ng mouse EGF in 25 µL incubation buffer; 320 nmol/L) or in the absence of unlabeled mouse EGF. With a final incubation volume of 150 µL, the mixture was incubated for 2 h at 22 C. The reaction was terminated by adding chilled buffer containing 10 mmol/L Tris-HCl and 25% polyethylene glycol followed by centrifugation at 4000 x g for 30 min. The supernatant was aspirated, and the pellet containing bound EGF was counted for 10 min in a {gamma}-counter with a counting efficiency of 97% for 125I.

The amount of plasma cell membrane protein that produced optimal binding was determined. Increasing amounts of myometrial membrane preparation were incubated with 20,000 cpm (0.4 nmol/L) [125I]hEGF at 4 C for 2 h (n = 4 for each concentration). To assess the optimal time and temperature conditions for EGF binding, we incubated 250 µg myometrial membrane protein (the amount determined to give optimal binding) with 20,000 cpm (0.4 nmol/L) [125I]hEGF at 4, 22, and 37 C for 30 min and 1, 2, 4, and 12 h. Having established the optimal binding conditions, saturation binding assays for EGF receptors were performed separately and individually for each specimen of myometrium, placenta, decidua, amnion, and chorion. Increasing quantities of [125I]hEGF, ranging from 10,000–60,000 cpm (0.2–1.2 nmol/L), were used to determine saturability. For each tissue sample, a minimum of five concentrations were evaluated in duplicate.

Statistical analysis

Receptor binding for each tissue was individually analyzed by Scatchard plot (35) to obtain the number of binding sites and the association (Ka) and dissociation (Kd) constants. For myometrium and decidua, the mean ± SEM between women not in labor (elective cesarean section) and those in labor (cesarean section after the onset of labor) were compared using both parametric (nonpaired t test) and nonparametric tests (Mann-Whitney rank sum test). For placenta, amnion, and chorion, the mean ± SEM of the binding parameters in the three groups of women studied (before labor, during labor, and after vaginal delivery) were also compared using both parametric (one-way ANOVA with Bonferroni correction) and nonparametric tests (Kruskal-Wallis ANOVA with Newman-Keuls multiple comparison). For all statistical evaluations, a two-tailed P value of 0.05 or less was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Optimization of assay conditions

Specific binding for EGF increased progressively with increasing amounts of myometrial plasma membrane protein used. The specific binding increased from 0.67 ± 0.21% (mean ± SEM) with 25 µg plasma membrane protein to 8.80 ± 1.09% with 250 µg plasma membrane protein. Based on this and the amount of tissue that can be practically obtained, 250 µg plasma membrane protein would allow sufficient binding yet permit enough points for saturation analysis to be performed to obtain reliable Scatchard analysis. Binding was optimal at 22 C for 2 h of incubation (Table 1Go). At 4 C, binding remained significantly lower than at 22 C for up to 12 h or at 37 C for up to 8 h of incubation. Binding at 22 and 37 C were comparable, but decreased significantly by 12 h at 37 C, possibly due to prolonged thermal degradation. Therefore, all saturation binding analyses of EGF receptors were carried out at 22 C for 2 h.


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  		Table 1. Effects of time and temperature on mean ± SEM specific binding of EGF (percentage) in pregnant human myometrium

 
Saturation binding assays

In each of the tissues studied, there was specific EGF binding that was saturable. Scatchard analysis consistently gave linear plots, suggesting a single class of EGF-binding sites in these tissues. Figures 1Go-5 are representative Scatchard plots of EGF binding with plasma membranes from myometrium, decidua, placenta, chorion, and amnion obtained from women before and during labor and (when applicable) after vaginal delivery. The concentrations of EGF receptor in myometrium, chorion, and amnion, but not those in decidua or placenta, were significantly higher during active labor than before labor (Fig. 6Go). Concentrations of myometrial EGF receptor (mean ± SEM) increased from 5.6 ± 0.8 fmol/mg protein before labor to 11.1 ± 2.8 fmol/mg protein during active labor (P <= 0.05). Similarly, EGF receptor concentrations in chorion increased from 13.5 ± 1.7 fmol/mg protein before labor to 26.7 ± 3.0 fmol/mg protein during active labor (P <= 0.05). The binding affinity of EGF receptor in myometrium, decidua, placenta, and chorion did not change significantly with labor, as indicated by the Ka and Kd (Table 2Go).



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  		Figure 1. Scatchard plot of the saturation binding assay for EGF receptors in myometrium before and after labor. Rt, Number of binding sites.

 


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  		Figure 6. Mean ± SEM concentration (femtomoles per mg protein) of EGF receptor in myometrium, decidua, placenta, chorion, and amnion before and after the onset of labor and after vaginal delivery. The concentrations of EGF receptors in myometrium, chorion, and amnion increased significantly from before labor to during labor (*, P = <0.05). After vaginal delivery, the concentrations of EGF receptor decreased significantly from those present during labor (**, P = < 0.05).

 

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  		Table 2. Mean ± SEM dissociation constant of EGF binding to uteroplacental tissues before, during, and after labor

 
In amnion, EGF receptor increased from 12.8 ± 2.7 fmol/mg protein before labor to 33.0 ± 2.3 fmol/mg protein during active labor (P <= 0.05) and then significantly decreased to 5.9 ± 1.2 fmol/mg protein after vaginal delivery (P <= 0.05) compared to that during labor. There was a statistically significant increase in the Kd of EGF receptor binding after labor and vaginal delivery (1.29 ± 0.21 nmol/L) compared to that before the onset of labor (0.59 ± 0.16 nmol/L; P < 0.05; Table 2Go).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our study demonstrates that specific receptors for EGF are present in myometrium from human term pregnancy. The myometrium, chorion, and amnion had significantly higher concentrations of EGF receptors when the women were in labor than before the onset of labor. This up-regulation of available EGF receptor sites in the uterus and, therefore, increased myometrial sensitivity to EGF may contribute to the activation and maintenance of uterine contractility with the onset of labor. EGF in low concentrations induced rhythmical contractions of estrogen-primed rat uterine muscle in vitro (5). The contractions were probably mediated through eicosanoid production, as they could be partially abrogated by inhibiting cyclooxygenase with indomethacin or inhibiting lipoxygenase with nordihydroguaritic acid, or completely suppressed with both inhibitors (6). Through a receptor-mediated effect, EGF can induce the turnover of phosphatidylinositol, a major regulator of calcium homeostasis (36) and can therefore directly activate myometrial contraction. Thus, the uterotonic effect of EGF was enhanced when extracellular calcium levels were increased or was inhibited when the calcium channel blocker nifedipine was given (6).

Both EGF and its receptor are expressed in the amnion (37). EGF stimulates PGE2 production by the amnion by inducing PG synthase (38). Therefore, a 3-fold increase in EGF receptors in the amnion with labor followed by a decline at vaginal delivery to prelabor levels indicates a marked functional increase in EGF and EGF receptor-mediated activity in establishing active and progressive uterine activity during the first stage of labor. The significantly increased dissociation constant of amnionic EGF receptors after vaginal delivery is consistent with EGF receptor-mediated uterine contractility being more crucial during the first stage of labor, but less so at delivery, when the Ferguson reflex-mediated increase in oxytocin release becomes more dominant.

EGF receptors in the chorion were also up-regulated with labor. Through its receptors in the chorion, EGF could induce phosphorylation of lipocortin, a potent inhibitor of phospholipase A2 (39), leading to an increase in the latter’s activity and, therefore, increased availability of free arachidonic acid (40) as the substrate for eicosanoid production. Using freeze-fracture electron microscopy (41) or immunocytochemistry (19), EGF receptors were decreased in chorion after labor, apparently due to internalization of receptor-ligand complexes in microvesicles. However, unlike saturation ligand binding assay, immunocytochemistry and electron microscopy cannot precisely measure receptor concentrations and determine the binding kinetics of the EGF receptor.

The observed lack of changes of EGF binding in the placenta after labor and parturition is not altogether surprising. The human placenta of term gestation probably does not have an intact paracrine system involving EGF and its receptor. Whereas immunohistochemical studies have shown positive staining for both EGF and its receptor, the staining intensity of both diminishes with increasing gestational age (21, 42, 43). In the human placenta, the gene for EGF receptor is expressed (44, 45), but there is no report of expression of the EGF gene. EGF stimulates cytotrophoblast proliferation and functional differentiation of the syncytiotrophoblast in human placenta (46). Reduced EGF binding and EGF receptor gene expression in placentas from pregnancies complicated by intrauterine growth restriction or diabetes mellitus have been reported (44), but our subjects were free of these complications.

In conclusion, EGF-specific receptors are present in uteroplacental tissues from term human pregnancy. EGF receptor concentrations in the myometrium, chorion, and amnion are up-regulated with labor.



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  		Figure 2. Scatchard plot of the saturation binding assay for EGF receptors in decidua before and after labor. Rt, Number of binding sites.

 


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  		Figure 3. Scatchard plot of the saturation binding assay for EGF receptors in placenta before labor, during active labor, and after vaginal delivery. Rt, Number of binding sites.

 


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  		Figure 4. Scatchard plot of the saturation binding assay for EGF receptors in chorion before labor, during active labor, and after vaginal delivery. Rt, Number of binding sites.

 


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  		Figure 5. Scatchard plot of the saturation binding assay for EGF receptors in amnion before labor, during active labor, and after vaginal delivery. Rt, Number of binding sites.

 
Received May 13, 1996.

Revised July 17, 1996.

Revised August 21, 1996.

Accepted August 27, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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