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Endocrinology Vol. 138, No. 7 3042-3046
Copyright © 1997 by The Endocrine Society

ARTICLES

The Uterine Myometrium Is a Target for Increased Levels of Activin A during Pregnancy

Lawrence B. Draper, Huira Chong, Eileen Wang and Teresa K. Woodruff

Departments of Medicine and Neurobiology and Physiology and The Center for Reproductive Sciences, Northwestern University, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Teresa K. Woodruff, Tarry Building 15–716, 303 Chicago Avenue, Chicago, Illinois 60611.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Activin A is a dimeric protein hormone that regulates numerous cellular functions. A clear physiological role for this molecule in pregnancy is suggested by previous studies in the human, wherein activin A rises dramatically as women approach parturition. To determine whether the rodent is a suitable animal model for further studies of activin action during pregnancy, the serum concentration of activin A was measured in pregnant rats. Activin A was detected in the serum of pregnant rats, beginning on day 12, and the serum concentration rose progressively through gestation (22-fold) and dramatically (140-fold) in labor. The potential target tissues for circulating activin were then identified in two ways. First, iodinated activin was injected into pregnant rats, and the tissues targeted by labeled ligand were identified in vivo. A tissue targeted by activin A in the pregnant rat was the uterine myometrium. To determine the ligand specificity of the uterine myometrial cells, the uteri of pregnant rats were collected and analyzed by in situ ligand binding. 125I-activin A binding was specific for the uterus myometrium, and the ligand binding was competed by unlabeled activin A but not by inhibin A. This result suggests that the receptor in this tissue compartment is an activin-specific receptor. The production of abundant activin A and the ability of exogenous ligand to target the myometrium of the uterus provides a pathway by which activin could regulate uterine function during pregnancy.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ACTIVIN IS a dimeric protein hormone that acts in numerous cellular systems to promote hormonogenesis or to determine cell fate (reviewed in Refs. 1, 2). Two major activin isoforms exist: activin A is a homodimer of ßA-subunits and activin B is a homodimer of ßB-subunits (3). Heterodimers of a {alpha}-subunit that is dissimilar to either ß-subunit, results in a functional antagonist (in some cellular systems) called inhibin (1, 2, 3). In human pregnancy, activin A circulates and increases in the third trimester before labor (4, 5). Moreover, activin A is dramatically upregulated in women who present clinically with preterm labor and deliver within 48 h (6). Activin B is not detected in the maternal circulation; however, it is detected in fetal amniotic fluid and cord blood serum (4). Inhibin A also increases progressively in women approaching parturition and may participate (in concert with estradiol) in the suppression of FSH during human pregnancy (7). A clear role for activin A in the context of pregnancy has not been described; however, an association of activin with the labor process is suggested by the presence of the ligand during labor (normal and abnormal).

To further characterize the role of activin A in pregnancy, the circulating concentration and target tissues of activin A were explored during rat gestation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Materials
Recombinant human (rh) activin A (mol wt 28,000) was obtained from Dr. Jennie Mather, Genentech, Inc. The ligand was formulated in a buffer of 0.15 M NaCl and 0.05 M Tris, pH 7.4.

Animals
Rat serum was collected at 0900 h and 1800 h from rats fitted with indwelling jugular cannulas (Zivic Miller laboratory animals and husbandry, Zelienople, PA) on days 11–21 of gestation. Serum was stored at -80 C until assayed. All other animals were timed pregnant Sprague Dawley-derived female rats and were obtained from Harlan BioSciences (Indianapolis, IN). The animals were maintained on a 14-h light, 10-h dark schedule, with constant access to food and water before and during the study. All animal experimentation was conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals.

Activin A enzyme-linked immunosorbent assay (ELISA)
Activin A was measured using a one-step monoclonal antibody-based ELISA (2F8:6H5), as described elsewhere (8, 9). The coat antibody was used at a concentration of 4 µg/ml. The detect antibody (6H5) was conjugated with biotin. The standard [rh-activin A lot 36(I)] and rat activin A are identical. Standards, control samples, and diluted samples (1:5 or 1:10) were incubated overnight. The biotin conjugate was amplified by strepavidin-horseradish peroxidase addition, and the signal was produced by incubation with orthophenylene diamine and hydrogen peroxide addition. Signal was measured at 490 nM absorption. The assay limit of detection was 100 pg/ml. Native ligand diluted linearly and in parallel to the standard curve. The ELISA had an inter- and intraassay coefficient of variation of less than 11% and 10%, respectively (high and low serum samples). The assay does not cross-react with rh-activin B, rh-inhibin A, rh-inhibin, B rh-follistatin or {alpha}2-macroglobulin, TGFß1, TGFß2, TGFß3, FSH, LH, TSH, and GH (8).

Iodination of activin A
Rh-activin A was iodinated by a modified lactoperoxidase method. Briefly, 5 µg of ligand was diluted in 0.4 M NaAcetate, pH 5.6; and 0.5 nmol Na125I (0.5 nmol/mCi on calibration date), 0.5 IU lactoperoxidase, and 0.25 nmol H2O2 were added sequentially. The ligand was incubated at ambient temperature with intermittent vortexing for 5 min. The reaction was quenched with 450 µl PBS + 0.05% Tween 20 + 0.5% BSA (Intergene, Purchase, NY). A 10-µl aliquot of the precolumn fraction was removed for TCA precipitation. Free iodine was removed using Sephadex G-10 column chromatography (PD-10, Pharmacia Inc., Piscataway, NJ). The specific activity of the ligands used in the in situ ligand binding and in vivo targeting studies was approximately 100 µCi/µg.

In situ ligand binding
In situ ligand binding was performed as described previously (10). Briefly, 12-µm cryocut tissue sections were incubated for 3 h at room temperature in blocking buffer: DMEM:F12 (1:1), 20 mM HEPES, 0.05% cytochrome C, 0.3% BSA, 0.01 mg/ml phenylmethylsulfonyl fluoride, 0.01% bacitracin, and 0.4 µg/ml leupeptin. Slides were then incubated at room temperature overnight in the same buffer, containing 40 pM 125I-rh activin A, or in the presence of 40 nM excess homologous ligand (to define nonspecific background), or heterologous ligand (inhibin A; to define low-affinity binding to heterologous ligands to activin receptors). The slides were washed in PBS (2 x 1 sec), PBS (2 x 10 min), and fixed in 3.7% formalin, 2% glutaraldehyde (10 min); rinsed in water (4 x 1 sec; and allowed to dry. Dry slides were exposed to x-ray film for 1–14 days and then dipped in NTB-3 emulsion (Kodak, Rochester, NY).

Targeting study; small animal dosing
The protocol and times for this study were predicated on a previous study in the female rat (11, 12). One-half hour before treatment with iodinated hormone, animals received 50 mg sodium iodide (0.5 ml of a 10% solution) sc. This pretreatment was to minimize organ-specific uptake of radiolabeled iodine. Restrained, conscious animals received one bolus injection of iodinated rh-activin A (1 µg activin A = ~100 µCi/animal). Eight animals were injected with 125I-rh-activin A sc. Three animals were killed 10 min after injection, and five animals were killed 60 min after injection. Two separate experiments, with two lots of labeled ligands, were used in these studies. In vivo competition of the injected radioactive ligand was not possible because of a lack of sufficient quantities of rh-activin A. Specificity of binding in this experimental design is based on the specificity of cell type bound in repeated experiments, with separate iodinated preparations of ligand, and in numerous animals.

Tissue harvest and analysis
Animals were narcolized with CO2, and trunk blood was collected. The total radioactivity present in 100 µl blood sample was then quantitated using a {gamma} counter. Blood samples were centrifuged for 5 min at 10,000 x g. The uterus was collected and divided in half. One horn of the uterus was mounted in OCT for tissue sectioning. The other uterine horn was placed into a tube and processed as described below under TCA precipitation analysis.

Slides from the in situ ligand binding study, as well as in vivo targeting studies, were prepared in identical fashion. Four identical slides (adjacent sections) were prepared for each tissue or condition. Each set of slides was exposed to emulsion for different lengths of time (1–6 weeks). In this manner, the best exposure for low- and high-density binding sites could be assessed. Two separate experiments (2 separate iodinations) were done with tissues from 6 animals. At least 12 tissue sections per tissue were examined. Slides or films were examined by 2–3 independent investigators. Representative sections were photographed using a Carl Zeiss microscope and epiluminescent, brightfield, or darkfield optics.

Tissues also were examined for protein-associated radioactivity by TCA precipitation. Tissue samples were homogenized in 5 vol of 20 mM sodium acetate, pH 5, containing 1 mM EDTA and 1 mM PMSF. The resulting homogenate was transferred to polypropylene tubes. Total radioactivity in the sample was determined. Samples were then centrifuged at 12,000 x g for 15 min (4 C). TCA was added (equal vol 50%), incubated for 1 h on ice, and centrifuged for 5 min at 12,000 x g. Total material and the pellet were counted to determine the percentage of the total radioactivity that was TCA precipitable.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Activin A was measured in serum samples collected from pregnant rats at various times during pregnancy (cross-sectional study design) or from animals fitted with an indwelling venous catheter (longitudinal study design). Activin A was detected at low levels, beginning on day 12 of pregnancy (Fig. 1AGo). Serum activin A increased 22-fold during the final 6 days of rat pregnancy. Serum collected from animals killed on individual days during pregnancy extended findings from the longitudinal studies to early in gestation, laboring rats, and lactating rats. Activin A was not detected in serum collected from day-7 animals, was detected at low levels on day 15, and rose progressively on days 18 and 19 of gestation. Serum collected from animals in active labor had highly elevated activin A serum levels (70,000 pg/ml), which returned to basal levels (100–200 pg/ml) in lactating animals (Fig. 1BGo).



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  		Figure 1. Activin A, measured by ELISA, in serum collected from pregnant rats. A, Animals were fitted with an indwelling jugular cannula, and samples were taken at 0900 h and 1600 h. Activin A was measured, and the values are reported as mean ± SD for n = 3 animals. B, Animals (n = 2–5) were killed on selected days of pregnancy, and serum activin A was measured. The values are reported as mean ± SE. The y-axis differs between panels A and B. Samples diluted linearly and in parallel to the standard curve.

 
The ability of 125I-activin A to target the uterus in vivo was tested by injecting radiolabeled ligand into pregnant rats on day 18 of gestation. Ligand accumulation was measured in the uterus, and the fold change in counts was compared between the two times studied (10 min and 60 min). The trichloroacetic acid (TCA) precipitable fraction of ligand was examined to verify that the accumulated radioactivity was associated with protein and not degraded free iodine. The uterus accumulated ligand (10.4-fold increase in tissue-associated counts) and 92.0% (10 min) and 80.3% (60 min) of the radioactivity was TCA precipitable and, therefore, associated with protein and not free iodine. Tissue localization of labeled ligand was examined by exposure of uterine sections to autoradiographic emulsion and imaging of the exposed silver grains. Abundant activin accumulation (presence of cell-associated silver grains) was detected in the myometrium of the uterus (Fig. 2Go). Low or no uptake of ligand was observed in the endometrial uterine layer.



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  		Figure 2. Emulsion-dipped, autoradiographic images of tissue sections that accumulate 125I-activin A after injection of ligand sc on day 18 of pregnancy. A–C, Darkfield images of grains accumulating in the myometrial layer (arrows). Adjacent areas that do not accumulate ligand are the endometrium. Photomicrographs are taken from different animals to show specificity of ligand targeting. M, Myometrium; E, endometrium; D, brightfield image of panel C; E, 200x magnification of myometrial and endometrial cells side by side. Myometrial nuclei are irregular, and the cells have grains associated with them. Endometrial nuclei are regularly shaped, and the cells do not have grains associated with them. F, 200x magnification of myometrial cells; G, 200x magnification of endometrial cells.

 
To extend these results, we examined the specificity of the uterus binding sites for activin A by competition of 125I-activin A binding to tissue sections in situ. Iodinated activin A bound the uterus myometrial layer, and the binding sites were activin A specific. The binding specificity was demonstrated by competition of the labeled ligand with unlabeled, excess activin A (1000-fold excess) but not with unlabeled, excess inhibin A (1000-fold excess) (Fig. 3Go). Day-15 and day-18 rat uterus tissue sections are illustrated, but activin binding was detected on all days examined (days 7, 21, and 22). There was little qualitative change in the ligand binding on any of the days compared. The ovary also was sectioned as a positive control. Specific activin binding sites (i.e. competed by unlabeled activin A) were localized to the corpus luteum and follicles of the ovary (Fig. 3Go). The endometrium of the uterus and stroma of the ovary did not bind labeled ligand.



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  		Figure 3. X-ray film images of adjacent tissue sections, probed with iodinated activin A. A–C, Day-15 pregnant rat uterus; D–F, day-18 pregnant rat uterus; G–I, day-15 pregnant rat ovary; A, D, and G, ISLB with 40 pM 125I-activin A; B, E, and H, ISLB with 40 pM 125I-activin A, competed with 50 nM activin A; C, F, and I, ISLB with 40 pM 125I-activin A, competed with 50 nM inhibin A. The dark silver areas indicate ligand binding to the myometrial layer of the uterus and corpora lutea and follicles of the ovary. The ligand is specifically competed by activin A and not by inhibin A. The uterus tissue sections shown in this figure were sectioned longitudinally. The outer areas, which are black, represent binding to the myometrium, and the central area, devoid of silver grain is the endometrium.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The role of activin in numerous cellular systems has been described. Activin regulates embryonic development, neuronal survival, hematopoietic stem cell fate, and hormonogenesis (1, 2). A role for activin in pregnancy has not been clearly established; however, experimental evidence supports some functional significance associated with this hormone in this physiological condition. First, ßA-subunit messenger RNA (mRNA) is produced in human and rat decidua tissue (13, 14, 15). In the antimesometrial rat decidua, activin A subunit mRNA is expressed on day 11 of psuedopregnancy. The increase in activin subunit mRNA is concomitant with a fall in follistatin mRNA in these same cells. Follistatin is a bioneutralizing binding protein of activin, and down-regulation of follistatin allows activin to regulate cellular responses. In mesometrial decidualized cells, activin A subunit is detected at relatively low levels until the late stages of gestation. Follistatin is expressed in the mesometrial decidua and can prevent activin A from up-regulating its own gene (13, 14, 15).

In humans, activin A increases in abundance in maternal circulation during normal pregnancy and rises further during labor (4, 5). Activin A serum levels drop to normal cycle levels after delivery (i.e. less than the lowest standard in our assay). Four- to 5-fold higher activin A serum concentration is detected in women who have preterm labor and delivery, compared with women having normal labor (6).

In the present study, activin A was measured in the serum of pregnant rats. Similar to the human, rat activin A became detectable and increased in the last half of pregnancy. Activin A increased 22-fold from midgestation to the day preceding labor. A further increase in activin A levels (140-fold) was measured in animals in active labor. The dramatic rise in activin A serum levels in laboring animals could be caused by the additive effect of activin A produced by both the antimesometrial and mesometrial decidua in late pregnancy. Alternatively, activin A production may stay constant, and the apparent rise in binding-protein free activin may result from falling follistatin levels.

The role of the circulating activin A, detected in both human and rats in late gestation, is not known. Activin is known to stimulate FSH from the anterior pituitary gland (3). FSH rises in the last half of rat pregnancy; however, FSH does not increase in the third trimester of human pregnancy. Nonpituitary target tissues and potential roles for activin during pregnancy may implicate this ligand in functions other than those associated with gonadotropin regulation.

As a means of addressing this hypothesis and investigating the potential target tissues for circulating (or paracrine acting) activin, binding sites for activin A were localized in tissues from pregnant rats. The uterine myometrium accumulated iodinated activin A when the ligand was delivered into the circulation. By in situ ligand binding, the binding sites were activin specific. Because inhibin did not bind the uterus myometrium, it is likely that the activin is binding to receptor, rather than to follistatin.

The two types of techniques used to localize activin binding sites are complementary, yet they address separate issues. The in situ ligand binding study results address the specific binding sites that may be involved in either paracrine or endocrine ligand signals. Indeed, it is plausible that activin produced by the decidua regulates the uterine myometrium in a paracrine-acting manner. In vivo targeting requires that a systemic (or endocrine) signal is capable of accessing and binding a particular target tissue(s). Based on our results, it is possible that circulating activin (regardless of source) is capable of binding the uterine myometrium during pregnancy. Second, in situ ligand binding allows investigation of specificity of the signal by competition with homologous and heterologous ligands.

The specific ligand binding and in vivo targeting of activin to the myometrium of the uterus during pregnancy, a time when activin A circulates in abundance, is novel. Activin binding sites in the cycling rat uterus also have been identified; however, in the absence of local or circulating ligand, it is unclear what the functional significance of these receptors may be during the cycle (16). A direct action of activin on the myometrium or any other muscle tissue has not previously been characterized. These results suggest that an important new avenue of investigation is in the regulation of uterine myocytes by activin A. Possible roles for this ligand include regulating uterine oxytocin (OT) or OT receptor. Activin inhibits OT production by luteinized granulosa cells (17), whereas central administration of activin regulates suckling-induced OT release (18). Whether activin is able to regulate OT/OT receptor in the uterus is unknown. Though the functional significance of activin is unresolved, this study suggests that activin may be one of a cascade of regulating molecules that participates (either directly or indirectly, stimulatory or inhibitory) in mammalian parturition and is an important factor to examine in this complex physiological setting.


   Acknowledgments
 
The authors thank Pacita Keh for confirmation of tissue binding sites and Vanessa Jones for help with the artwork.

Received November 13, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Woodruff T, Mather J 1995 Inhibin, activin and the female reproductive axis. Annu Rev Physiol 57:219–244[CrossRef][Medline]
  2. Mathews L 1994 Activin receptors and cellular signaling by the receptor serine kinase family. Endocr Rev 15:310–325[CrossRef][Medline]
  3. Vale W, Rivier C, Hsueh A, Campen C, Meunier H, Bicsak T 1988 Chemical and biological characterization of the inhibin family of protein hormones. Recent Prog Horm Res 44:1–34
  4. Petraglia F, Garg S, Florio P, Sadick M, Gallinelli A, Wong W-L, Krummen L, Comitini G, Mather J, Woodruff T 1993 Activin A and activin B measured in maternal serum, cord blood serum and amniotic fluid during human pregnancy. Endocrine J 1:323–327
  5. Woodruff T, Sluss P, Wang E, Janssen I, Mersol-Barg M 1997 Activin A, activin B, and follistatin are dynamically regulated during human pregnancy. J Endocrinol 152:167–174[Abstract/Free Full Text]
  6. Petraglia F, De Vita D, Gallinelli A, Aguzzoli L, Genazzani A, Romero R, Woodruff T 1995 Abnormal concentration of maternal serum activin-A in gestational diseases. J Clin Endocrinol Metab 80:558–561[Abstract]
  7. Muttukrishna S, George L, Fowler P, Groome N, Knight P 1995 Measurement of serum concentrations of inhibin-A (alpha-beta A dimer) during human pregnancy. Clin Endocrinol (Oxf) 42:391–397[Medline]
  8. Wong W, Garg S, Woodruff T, Bald L, Fendly B, Lofgren J 1993 Monoclonal antibody based ELISAs for measurement of activins in biological fluids. J Immunol Methods 165:1–10[CrossRef][Medline]
  9. Woodruff T, Krummen L, Baly D, Garg S, Allison D, Sadick M, Wong W, Mather J, Soules M 1993 Quantitative two-site enzyme-linked immunosorbent assays for inhibin A, activin A, and activin B. Hum Reprod 8:133–137[Abstract/Free Full Text]
  10. Jakeman L, Mather J, Woodruff T 1992 In vitro ligand binding of 125I-recombinant human activin A to the female rat brain. Endocrinology 131:3117–3119[Abstract]
  11. Woodruff T, Krummen L, Chen S, DeGuzman G, Lyon R, Baly D, Allison D, Garg S, Wong W, Hebert N, Mather J, Cossum P 1993 Pharmacokinetic profile of recombinant human (rh) inhibin A and activin A in the immature rat: I. Serum profile of rh-Inhibin A and rh-Activin A in the immature female rat. Endocrinology 132:715–724[Abstract]
  12. Woodruff T, Krummen L, Chen S, Lyon R, Hansen S, DeGuzman L, Covello R, Mather J, Cossum P 1993 Pharmacokinetic profile of recombinant human (rh) inhibin A and activin A in the immature rat: II. Tissue distribution of 125I-rh-inhibin A and 125I-rh-activin A in immature female and male rats. Endocrinology 132:725–734[Abstract]
  13. Gu Y, Gibori G 1995 Isolation, culture, and characterization of the two cell subpopulations forming the rat decidua: differential gene expression for activin, follistatin, and decidual prolactin-related protein. Endocrinology 136:2451–2458[Abstract]
  14. Gu Y, Srivastava R, Ou J, Krett N, Mayo K, Gibori G 1995 Cell-specific expression of activin and its two binding proteins in the rat decidua: role of alpha 2-macroglobulin and follistatin. Endocrinology 136:3815–3822[Abstract]
  15. Petraglia F, Woodruff T, Botticelli G, Botticelli A, Genazzani A, Mayo K, Vale W 1992 Gonadotropin-releasing hormone, inhibin, and activin in human placenta: evidence for a common cellular localization. J Clin Endocrinol Metab 74:1184–1188[Abstract]
  16. Woodruff T, Krummen L, McCray G, Mather J 1993 In situ ligand Binding of [125I]activin-A and recombinant human[125I] inhibin-A to the adult rat ovary. Endocrinology 133:2998–3006[Abstract]
  17. Shukovski L, Findlay J 1990 Activin-A inhibits oxytocin and progesterone production by preovulatory bovine granulosa cells in vitro. Endocrinology 126:2222–2224[Abstract]
  18. Plotsky P, Sawchenko P, Vale W Evidence for inhibin ß-chain like-peptide mediation of suckling-induced oxytocin secretion. Program of the 18th Annual Meeting of The Society for Neuroscience, Toronto, Ontario, Canada, 1988, p 627



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