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BOR - Papers in Press, published online ahead of print January 25, 2006.
Biol Reprod 2006, 10.1095/biolreprod.105.044917
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BIOLOGY OF REPRODUCTION 74, 850–856 (2006)
DOI: 10.1095/biolreprod.105.044917
© 2006 by the Society for the Study of Reproduction, Inc.

Research Article

Expression of Nerve Growth Factor and Its Receptors NTRK1 and TNFRSF1B Is Regulated by Estrogen and Progesterone in the Uteri of Golden Hamsters1

Zhanquan Shi 34 , Koji Y. Arai 5, Wanzhu Jin 34 , Qiang Weng 6, Gen Watanabe 34 , Akira K. Suzuki 7, and Kazuyoshi Taya 2 34 

Department of Basic Veterinary Science,3 The United Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan Laboratory of Veterinary Physiology,4 Department of Veterinary Medicine, Department of Tissue Physiology,5 Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183-8509, Japan Faculty of Biological Science and Technology,6 Beijing Forestry University, Beijing 100083, China PM2.5/DEP Research Project,7 National Institute of Environmental Studies, Ibaraki 305-8506, Japan

ABSTRACT

Experiments were conducted using female golden hamsters to identify the presence of nerve growth factor (NGF) and its receptors NTRK1 and TNFRSF1B in the uteri of female animals and regulation on their expression by estrogen and progesterone. NGF and its receptor NTRK1 were immunolocalized to luminal epithelial cells, glandular cells, and stromal cells. TNFRSF1B was immunolocalized in luminal epithelial and glandular cells, with no staining found in stromal cells of the uterine horns of normal cyclic golden hamsters. Strong immunostaining of NGF and its receptors NTRK1 and TNFRSF1B was observed in uteri on the day of proestrus as compared to the other stages of the estrous cycle. Results of immunoblot analysis of NGF revealed that there was a positive correlation between uterine NGF expression and plasma concentrations of estradiol-17ß. To clarify the effects of estrogen and progesterone on NGF, NTRK1, and TNFRSF1B expression, adult female golden hamsters were ovariectomized and treated with estradiol-17ß and/or progesterone. Immunoblot analysis and immunohistochemistry indicated that estradiol-17ß stimulated expression of NGF and its two receptors in the uterus. Treatment with progesterone also increased NGF and NTRK1 expression in the uterus. However, no additive effect of these steroids on expression of NGF and its receptors was observed. Changes in uterine weights induced by estradiol-17ß and/or progesterone showed the same profile with that of NGF, suggesting that a proliferative act of NGF may be involved in uterine growth. These results suggest that NGF may play important roles in action of steroids on uterine function.

estrous cycle, female reproductive tract, golden hamster, growth factors, nerve growth factor, NTRK1, receptor, steroid hormones, TNFRSF1B, uteri, uterus

INTRODUCTION

Nerve growth factor (NGF), a 26-kDa polypeptide [1], belongs to a family of related proteins required for the survival, maintenance, and development of discrete neuronal populations in the central and peripheral nervous systems [2, 3]. NGF initiates its biological roles by binding two different membrane-spanning receptors. One is the high-affinity receptor NTRK1 (previously known as trkA), a 140-kDa transmembrane tyrosine kinase receptor encoded by members of the trk proto-oncogene family [4–6]. The other is the low-affinity receptor known as TNFRSF1B (previously known as p75), a 75-kDa glycoprotein that belongs to the family of tumor necrosis receptor [7]. TNFRSF1B can also be recognized with low affinity by all other neurotrophins, including brain-derived neurotrophic factor (BDNF), NTF3, and NTF5 [4]. NGF preferentially binds the NTRK1 receptor with high affinity [8, 9], while the TNFRSF1B can potentiate or inhibit NTRK1-mediated biological responses [10–12].

The uterus is innervated by sympathetic neurons that are involved in the regulation of uterine blood flow [13–15]. In many mammalian species, pregnancy induces denervation of the uterus [15, 16]. Nerve fiber density of the uterus is also altered during the estrous cycle. Steroid hormones are thought to be responsible for these changes. In fact, estrogen stimulates innervation of the uterus [16]. NGF was postulated to be a mediator of the effects of steroids on the uterine nervous system because estrogen increases uterine NGF expression [17]. Furthermore, uterine NGF concentrations decrease during the mid- and late pregnancy in the rat [18]. These studies suggest that uterine NGF has roles in the regulation of uterine innervation. Although initial observations led to the conclusion that the biological actions of NGF were limited to the nervous system [6, 19], emerging evidence suggests that NGF can also act on nonneural cells, including the cells of the immune [20–22] and endocrine [23–25] systems. Reports indicated that both NGF and its receptors NTRK1 and TNFRSF1B are expressed and can exert their biological roles in the female reproductive system [26–28]. However, most of the studies focused on their roles in the ovary [27, 29–32]. Little is known about their expression and regulation in other female reproductive organs.

The uterus undergoes a definite sequence of changes during the estrous and reproductive cycles. The most prominent morphological changes noted in the uterus during the estrous cycle are in the endometrium and its associated glands. Estrogen and progesterone are considered to be, to a large extent, responsible for the changes [33, 34]. In the present study, to elucidate involvement of NGF system in the regulation of uterine function outside the nervous system, we examined the expression and distribution patterns of NGF and its receptors in uteri of golden hamsters during the normal estrous cycle and the role of estrogen and progesterone in regulation of expression of NGF and its receptors in uteri.

MATERIALS AND METHODS

Animals

Adult healthy female golden hamsters (Mesocricetus auratus) were housed under controlled temperature (23–25°C) and lighting (lights on from 0500 to 1900 h). Food and water were available ad libitum. The 4-day estrous cycle was determined by the presence of a characteristic vaginal discharge on the morning of the day of ovulation, which was designated as Day 1 of the estrous cycle. Golden hamsters with at least two consecutive 4-day estrous cycles were used in the present study. All experimental procedures were carried out in accordance with the Guide for the Care and Use of Laboratory Animals prepared by Tokyo University of Agriculture and Technology.

Treatments

In the present study, two experiments were conducted. In experiment 1, we set five time point as 1100 h of Day 1 to Day 4 and 1700 h of Day 4 across the estrous cycle; at each time point five intact hamsters were used. In experiment 2, 20 hamsters were ovariectomized under ether anesthesia and treated with steroid hormones. Steroid hormones were administered 2 wk after the surgery. The animals were divided into four groups (five hamsters each group) and subcutaneously injected with either estradiol-17ß (10 µg in 200 µl sesame oil) or progesterone (500 µg in 200 µl sesame oil) or both (10 µg estradiol-17ß and 500 µg progesterone in 200 µl sesame oil). Control animals received an injection of 200 µl sesame oil. Each animal received the injections at 1100 h for 2 consecutive days.

Sampling

In experiment 1, blood samples were taken by decapitation at 1100 h on each day of the estrous cycle and at 1700 h on Day 4, respectively. Uteri were recovered and processed for immunohistochemistry and immunoblot analysis. Plasma samples were separated by centrifugation at 1700 x g at 4°C for 15 min and stored at –20°C until assayed for estradiol-17ß and progesterone. In experiment 2, animals were killed by decapitation 24 h after the second injection of steroid hormones, and uteri were recovered. After removing intrauterine fluid, wet weights of uteri were measured and processed for immunoblot analysis and immunohistochemistry.

Immunohistochemical Detection of NGF and Its Receptors NTRK1 and TNFRSF1B in the Uterus

Uterine samples were immediately fixed in 4% paraformaldehyde in 0.05 M PBS, pH 7.4, and embedded in paraffin. The paraffin-embedded tissues were serially sectioned at 6-µm thickness and mounted on poly-L-lysine-coated glass slides for more than 24 h at 32°C. The procedures for immunohistochemistry were described previously [35]. NGF and its receptors NTRK1 and TNFRSF1B were detected by using polyclonal antibodies against NGF (0.4 µg/ml, M-20), NTRK1 (2 µg/ml, 763), and TNFRSF1B (2 µg/ml, H-92) (Santa Cruz Biotechnology, Santa Cruz, CA) to identify NGF, NTRK1, and TNFRSF1B, respectively. The specificity of the antibodies was examined using normal rabbit IgG (sc-2027, Santa Cruz Biotechnology) instead of primary antibodies.

Radioimmunoassay of Estradiol-17ß and Progesterone

Plasma concentrations of estradiol-17ß and progesterone were determined by double-antibody radioimmunoassay systems using 125I-labeled radioligands as described previously [36]. Antisera against estradiol-17ß (GDN 244) [37] and progesterone (GDN 337) [38] was kindly provided by Dr. G. D. Niswender (Animal Reproduction and Biotechnology, Colorado State University, Fort Collins, CO). The intra- and interassay coefficients of variation were 3.7% and 6.2% for estradiol-17ß and 6.3% and 15.4% for progesterone, respectively.

Immunoblot Analysis of NGF

Freshly isolated uteri were immediately put in lysis buffer (137 mM NaCl, 20 mM Tris-HCl [pH 8.0], 1% Nonidet P-40, 10% glycerol, 1 mM PMSF, 10µg/ml aprotinin, 1 µg/ml leupeptin, 0.5 mM sodium vanadate) in centrifuge tubes and homogenized on ice using a homogenizer (Phiscotoron, Nichion, Tokyo, Japan). The homogenized mixtures were centrifuged at 25000 x g for 15 min at 4°C. The insoluble debris was removed, and the protein concentrations of the extracts were determined using Bio-Rad protein assay (Bio-Rad Laboratories). Each sample containing 20 µg protein was separated by 10% SDS-PAGE. Thereafter, protein bands of samples were electrically transferred on a PVDF membrane (Immobilon-p Transfer Membrane, Millipore Corporation, Billerica, MA). After blocking with 5% skim milk in Tris-buffered saline containing 0.05% Tween 20 (10 mM Tris-HCl, pH 8.0, 150 mM NaCl, 0.05% Tween 20; TBST) overnight at 4°C, the membrane was incubated with polyclonal antibody against NGF at a concentration of 0.2 µg/ml (M-20, Santa Cruz Biotechnology) in 5% skim milk in TBST. After washing with TBST for 5 min twice, the membrane was incubated with a horseradish peroxidase-conjugated anti-rabbit IgG antibody (1:2000; Cell Signaling, Beverly, MA) diluted with 5% skim milk in TBST. After washing the membrane with TBST for 5 min twice, immunoreactivity was detected by using an enhanced chemiluminescent detection reagent (ECL Western blotting detection reagent; Amersham Pharmacia Biotech, Buckinghamshire, UK) according to the manufacturer protocol. The images were analyzed using NIH image 1.62 to determine their relative intensity.

Statistics

All data were expressed as mean ± SEM. To compare the mean values, results were subjected to one-way ANOVA followed by the Duncan multiple range test [39]. A value of P < 0.05 was considered to be statistically significant. The correlation between parameters was determined using simple regression analysis.

RESULTS

Immunohistochemistry of NGF and Its Receptors NTRK1 and TNFRSF1B in the Uteri of Cyclic Golden Hamsters

Representative sections showing immunohistochemical localization of NGF, NTRK1, and TNFRSF1B are shown in Figure 1. The results of the immunohistochemistry described here are summarized in Table 1. In the uteri of normal cyclic golden hamsters, immunopositive signals for NGF were detected in luminal and glandular epithelium and stromal cells (Fig. 1, e–h). In luminal epithelial cells and stromal cells, immunopositive signals for NGF were weak on Day 2 but strong on Day 4 of the estrous cycle. By contrast, staining intensity in glandular epithelium did not change during the estrous cycle. Immunolocalization of NTRK1 was similar to that of NGF (Fig. 1, i–l). No signal for TNFRSF1B was found in stromal cells, while strong immunoreactivity was detected in luminal and glandular epithelium on Day 4 of the estrous cycle (Fig. 1, m–p).


Figure 1
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  		FIG. 1. Immunohistochemical localization of NGF and its receptors, NTRK1 and TNFRSF1B, in uteri of cyclic golden hamsters. The first row (a–d) are figures stained by normal rabbit IgG for samples through Day 1 to Day 4 of the estrous cycle; the second row (e–h), the third row (i–l), and the bottom row show immunostaining of NGF, NTRK1, and TNFRSF1B, respectively, in uteri of normal cyclic golden hamsters recovered on Days 1 (e, i, m), 2 (f, j, n), 3 (g, k, o), and 4 (h, l, p) of the estrous cycle. Insets in panels g, h, m, and p show uterine gland of that time point with same magnification. le, Luminal epithelium; ge, glandular epithelium; sc, stromal cells. Bar = 50 µm.


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  		TABLE 1. Relative abundance of NGF, NTRK1, and TNFRSF1B in uteri during the estrous cycle of the golden hamster.a

Immunoblot Analysis of NGF in Uteri of Cyclic Golden Hamsters

Immunoblot analysis for NGF revealed that NGF expression in the uterus significantly changed during the estrous cycle. Levels of NGF showed the lowest value on Day 2 and increased until 1700 h on Day 4 (Fig. 2a).


Figure 2
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  		FIG. 2. Immunoblot analysis of NGF in uteri of cyclic golden hamsters (a) and plasma concentrations of estradiol-17ß (solid lines with closed cycle) and progesterone (dotted lines with open cycle) during the estrous cycle of intact golden hamsters (b). Values represent means ± SEM. Bars with different letters are significantly different (P < 0.05).

Plasma Concentrations of Estradiol-17ß and Progesterone During the Estrous Cycle

Plasma concentrations of estradiol-17ß increased from Day 1 through 1700 h on Day 4 and reached the peak level. Plasma concentrations of progesterone remained at relatively high levels on Days 1 and 2 and decreased to very low levels by the morning of Day 3. Thereafter, plasma concentrations of progesterone noticeably increased at 1700 h on Day 4 (Fig. 2b). There is a positive correlation found (r = 0.745, P < 0.01) between plasma levels of estradiol-17ß and uterine NGF expression during the estrous cycle.

Immunohistochemistry of NGF and Its Receptors NTRK1 and TNFRSF1B in Uteri of Ovariectomized Golden Hamsters Treated with Steroid Hormones

The pictures of immunohistochemical detection of NGF, NTRK1, and TNFRSF1B in uteri of ovariectomized golden hamsters were shown in Figure 3 and summarized in Table 2. Administration of estradiol-17ß noticeably increased the immunostaining intensity of NGF in epithelial cells and stromal cells in uteri in either the presence or the absence of progesterone treatment (Fig. 3, e–h). The strongest signals for NGF were found in uteri treated with estradiol-17ß alone (Fig. 3f), whereas immunostaining for NGF was relatively low in uteri obtained from control animals (Fig. 3e). Treatment with progesterone alone did not affect uterine NGF expression (Fig. 3g). The expression pattern of NTRK1 in glandular cells was similar to that of NGF. Both estradiol-17ß and progesterone increased the staining intensity for NTRK1 in luminal epithelium, with stronger staining in uteri treated with estradiol-17ß than those treated with progesterone (Fig. 3, i–l). Treatment with estradiol-17ß had no effect on the staining intensity of NTRK1 in stromal cells (Fig. 3j). The staining of NTRK1 in stromal cells was enhanced by progesterone treatment in the either absence or the presence of administration of estradiol-17ß (Fig. 3, k and l). Strong induction of TNFRSF1B in luminal and glandular epithelium was found in uteri treated with estradiol-17ß alone. However, the effect of estradiol-17ß on TNFRSF1B expression was not observed when progesterone was administered simultaneously (Fig. 3, m–p). Treatment with progesterone alone did not affect uterine TNFRSF1B expression (Fig. 3, o and p).


Figure 3
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  		FIG. 3. Immunohistochemical localization of NGF and its receptors, NTRK1 and TNFRSF1B, in uteri of ovariectomized golden hamsters. The first rows (a–d) are pictures stained by normal rabbit IgG for control, estradiol-17ß treatment, progesterone treatment, and estradiol-17ß plus progesterone treatment groups, respectively. The second row (e–h), third row (i–l), and bottom row (m–p) show immunostaining of NGF, NTRK1, and TNFRSF1B, respectively, in uteri of control (e, i, m), estradiol-17ß (f, j, n), progesterone (g, k, o), and estradiol-17ß plus progesterone (h, l, p) groups. Insets in panels e, g, i, k, l, m, and p show uterine gland of that time point with same magnification. le, Luminal epithelium; ge, glandular epithelium; sc, stromal cells. Bar, 50 µm.


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  		TABLE 2. Relative abundance of NGF, NTRK1, and TNFRSF1B in uteri of ovariectomized golden hamsters treated with ovarian steroids.a

Changes in Uterine Weights of Ovariectomized Golden Hamsters Treated with Steroid Hormones

Uterine weights of ovariectomized golden hamsters are shown in Figure 4a. All treatments with steroid hormones significantly increased uterine weights compared to the control group, with less effects of progesterone than that of estradiol-17ß. Any additive effect of the steroids on uterine weights was not observed.


Figure 4
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  		FIG. 4. Effects of ovarian steroids on uterine weights (a) and on NGF protein expression in uteri of ovariectomized hamsters (b). Values represent means ± SEM. Bars with different letters are significantly different (P < 0.05). C, Controls received vehicle; E, treated with estradiol-17ß; P, treated with progesterone; EP, treated by estradiol-17ß and progesterone together.

Immunoblot Analysis of NGF in Uteri of Ovariectomized Golden Hamsters Treated with Estradiol-17ß and/or Progesterone

Immunoblot analysis of NGF in uteri recovered from ovariectomized golden hamsters are shown in Figure 4b. Both estradiol-17ß and progesterone increased expression of NGF as compared to control. The effect of estradiol-17ß was greater than that of progesterone. No additive effect of progesterone and estradiol-17ß was observed.

DISCUSSION

The present study is the first to report the expression patterns of NGF and its two receptors NTRK1 and TNFRSF1B in uteri of female golden hamsters during the estrous cycle and the regulation of their expression by estrogen and progesterone.

In uteri of cyclic hamsters, immunolocalization of NGF and NTRK1 were detected in luminal and glandular epithelium and stromal cells of endometrium. Immunostaining of TNFRSF1B was found in luminal and glandular epithelium but not in stromal cells. This distribution pattern of NGF in golden hamsters was obviously different from that found in mice. In murine uteri, NGF immunoreactivity was localized in epithelial cells and part of stromal cells (not all stromal cells) of the uterine endometrium [40]. Immunolocalization of NGF receptors NTRK1 and TNFRSF1B in uteri of other animals has not been reported. Strong immunostaining of NGF and its receptors NTRK1 and TNFRSF1B was found in uteri on the day of proestrus. Immunoblot analysis of NGF indicated that the maximal expression of NGF occurred at 1700 h on the day of proestrus when plasma concentrations of both estradiol-17ß and progesterone reached the peak levels. The changing pattern of NGF in the uterus was positively correlated with that of plasma concentrations of estradiol-17ß during the estrous cycle. Past work using PC12 cells has indicated that NGF exerts most of its actions by binding to its receptor NTRK1 and stimulating NTRK1 dimerization and autophosphorylation of tyrosine residues [8, 41, 42]. Phosphorylation of NTRK1 leads to activation of second-messenger cascades including mitogen-activated protein kinase and phosphatidylinositol-3 kinase, two pathways that are important for cell differentiation and survival [42–46]. The results of the immunohistochemistry in the present study strongly suggest paracrine or autocrine roles of NGF through binding to its two receptors NTRK1 and TNFRSF1B in the uterine proliferation and growth during the estrous cycle and the regulation of their expression by ovarian steroids. The present experiments using ovariectomized hamsters clearly demonstrated that both estradiol-17ß and progesterone significantly stimulated proliferation of the uterus and expression of uterine NGF. The stimulatory effect of estradiol-17ß was greater than that of progesterone, and there was no synergistic interaction between estradiol-17ß and progesterone. The changes in uterine weight after the steroid treatments were parallel to the changes in uterine NGF expression, suggesting that NGF may mediate the effects of steroids on uterine weights. The stimulatory effects of estradiol-17ß and progesterone on NGF expression have been reported in the uteri of mice [40]. Although, previous studies suggest that uterine NGF is involved in the regulation of uterine innervation [17, 18], the present study demonstrated localization of NGF receptors in uterine nonneural cells. The localization patterns of NGF receptors and regulation of their expression by steroid hormones strongly indicate that uterine NGF is involved the regulation of uterine remodeling during the estrous cycle.

It has been reported that NGF was involved in growth and differentiation of a wide variety of tissues. For example, NGF has been shown to have proliferative activity in brain capillary endothelial cells [47], myogenic cells [48], bladder smooth muscle cells [44], and corneal epithelial cells [49]. In another study, a relationship between NGF and estrogen was reported in the process of cell proliferation in human urothelial cell (HUC) culture. Estrogen stimulated both proliferation and NGF synthesis in HUC culture, and NGF was shown to stimulate HUC proliferation. Furthermore, the proliferation of HUC stimulated by estrogen was abolished by NGF antiserum or NTRK1 antagonist k252a [50]. Therefore, the proliferation of HUC after treatment with estrogen was at least partly mediated by NGF. As commonly known, estrogen and progesterone are considered to be largely responsible for growth and proliferation of the uterus during the estrous cycle. The stimulating effects of estrogen and progesterone on NGF expression in this study suggest that estrogen and/or progesterone may act synergistically with NGF on uterine proliferation and growth, and it has been speculated that the mechanisms involve putative estrogen response elements in the regulatory regions of NGF and its receptors [51–53].

The expression and distribution patterns of NTRK1 and TNFRSF1B were different from those of NGF in uteri of ovariectomized golden hamsters treated with ovarian steroids. Estradiol-17ß predominantly stimulated expression of NTRK1 in luminal epithelial cells and expression of TNFRSF1B in epithelial and glandular cells, whereas progesterone mainly stimulated expression of NTRK1 in stromal cells. The weakened staining intensity of NTRK1 in epithelial cells and that of TNFRSF1B in epithelial and glandular cells by progesterone suggested that progesterone suppressed the stimulating effects of estrogen on NTRK1 and TNFRSF1B expression in uteri. Similar inhibitory effects of progesterone on estradiol-17ß actions have been documented in mouse uteri. Estradiol-17ß induced lactoferrin expression and epithelial DNA synthesis, and progesterone inhibited these actions [54, 55].

Although the stimulatory effects of estradiol-17ß and progesterone on NTRK1 and TNFRSF1B expression in uteri have not been reported in other animals, previous studies indicated that both estradiol-17ß and progesterone stimulated NTRK1 expression in neural cells [56–58].

In summary, the present study is the first to report that NGF and its two receptors NTRK1 and TNFRSF1B are present in uteri of golden hamsters and their expression is stimulated by estrogen and progesterone. These results suggest that NGF and its receptors may be involved in the regulation of uterine growth and proliferation during the estrous cycle.

ACKNOWLEDGMENTS

We are grateful to Dr. G. D. Niswender (Animal Reproduction and Biotechnology, Colorado State University, Fort Collins, CO) for antisera against estradiol-17ß (GDN 244) and progesterone (GDN 377).

FOOTNOTES

1 Supported by a Grant-in-Aid for COE Scientific Research (The 21st Century Center of Excellence Program, E-1) from the Ministry of Education, Culture, Sport, Science and Technology of Japan. Back

2 Correspondence: Kazuyoshi Taya, Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3–5–8, Saiwai-cho, Fuchu, Tokyo 183-8509, Japan. FAX: 81 42 367 5767; taya{at}cc.tuat.ac.jp Back

Received: 1 July 2005.

First decision: 2 August 2005.

Accepted: 23 January 2006.

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