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Research Article |
University of Duisburg-Essen,3 Institute of Anatomy, 45122 Essen, Germany
Department of Obstetrics and Gynecology,4 University of Illinois at Chicago, Chicago, Illinois 60612
ABSTRACT
The expression of human CYR61 (cysteine-rich, angiogenic inducer, 61; CCN1) mRNA has been previously shown to be deregulated in the endometrium of women with endometriosis. We have chosen the baboon model (Papio anubis) of induced endometriosis to clarify whether CYR61 mRNA upregulation is predisposed to an inappropriately differentiated endometrium or is deregulated as a response to the presence of ectopic lesions. In the baboon, endometrial CYR61 mRNA expression underwent moderate cyclical variation, with a significant 7.3-fold increase detected at Day 2 postmenses when compared to endometrium from the proliferative and secretory phases. The CYR61 transcript was extensively upregulated in the eutopic endometrium from all baboons with induced endometriosis, as early as 1 mo postinoculation of menstrual tissue into the peritoneal cavity. CYR61 mRNA expression then decreased throughout progression of the disease, but remained higher compared to control tissues. Ectopic endometriotic lesions showed a further increase in CYR61 mRNA, with highest expression found in red lesions. Moreover, the expression levels of CYR61 transcripts correlated significantly with those of VEGF. Immunohistochemistry revealed the presence of CYR61 protein in glandular and luminal epithelial cells as well as in blood vessels of eutopic and ectopic endometrium. As in humans, increased levels of CYR61 mRNA correlated with the development of endometriosis in baboons. The increase of CYR61 mRNA in eutopic endometrium of baboons following peritoneal inoculation with menstrual endometrium provides evidence for a feedback mechanism from resulting lesions to induce a shift in gene expression patterns in the eutopic endometrium.
estradiol, female reproductive tract, menstrual cycle, uterus
INTRODUCTION
Endometriosis is an estrogen-dependent gynecological condition that affects women of reproductive age (reviewed in [1]). The disease is characterized by the presence of endometrial tissue fragments outside the uterine cavity and is associated with pelvic pain, dysmenorrhea, and infertility [1]. Although multiple theories exist regarding the etiology of the disease, the implantation hypothesis of retrograde menstruation suggested by Sampson [2] is the most widely accepted. However, because retrograde menstruation occurs in all women, the reason for adhesion and persistence of endometriotic lesions in approximately 10% of women who develop the disease remains unsolved. It is possible that an inappropriately differentiated endometrium in women prone to the disease could cause the adhesion and establishment of endometrial tissues outside of the uterus. Furthermore, an enhanced local estrogen response in the ectopic endometrium could promote proliferation and differentiation as well as persistence [3].
In search of candidate genes involved in pathogenesis of endometriosis in humans, CYR61 mRNA expression has been shown to be increased in eutopic as well as ectopic endometrium in patients with endometriosis [4]. CYR61, a member of the CCN family of growth regulators, is a proangiogenic factor that mediates diverse roles in development, cell proliferation, and tumorigenesis (reviewed in [5]). Human CYR61 gene encodes a cysteine-rich secreted heparin-binding protein of 381 amino acids with a predicted molecular mass of 42 kDa [5]. Expression of CYR61 mRNA is rapidly induced in an immediate early fashion by a spectrum of stimuli such as growth factors, cytokines, and estrogens [6–8]. Regulation of CYR61 mRNA expression by estrogens has been described in eutopic endometria. However, the expression remains unchanged in lesions of women treated with a GnRH1 agonist; this suggests the existence of other regulatory factors besides ovarian hormones [4].
To clarify whether CYR61 mRNA upregulation is associated with an inappropriately differentiated endometrium or is deregulated as a response to the presence of ectopic lesions, we have used the primate model for endometriosis, which was first established by D'Hooghe et al. [9]. Baboons have menstrual cycles and endometrial gene expression patterns that are comparable to those of humans, and are known to develop endometriosis spontaneously, although not as frequently as do humans [10, 11]. Intraperitoneal inoculation of menstrual endometrial tissue resulted in endometriosis as defined by incidence of endometriotic lesions, histological criteria, and cycle fecundity [11, 12].
Here, we describe the expression pattern of CYR61 gene and protein in normal and endometriotic endometrium, as well as in ectopic endometriotic lesions, in baboons with experimentally-induced endometriosis and with spontaneously-developed disease.
MATERIALS AND METHODS
Animals and Induction of Endometriosis
In this study, a total of 27 female olive baboons (Papio anubis) were investigated. Twenty-four were born at and obtained from the Southwest Foundation for Biomedical Research. Three other baboons were wild-caught at the Institute of Primate Research, Nairobi, Kenya.
Endometrial tissues were obtained from 19 control, disease-free baboons during the menstrual (n = 3), proliferative (n = 3) and secretory (n = 13) phases of the menstrual cycle. Endometriosis was experimentally induced in six cycling baboons by intraperitoneal inoculation with menstrual endometrium on Day 2 of two consecutive menstrual cycles (where Day 1 was the first day of menses). Details of the inoculation have been previously described [12, 13]. An initial analysis of disease and CYR61 mRNA expression was done in two of the six animals at 1 mo following inoculation. In the remaining four animals, the progression of disease was monitored in each animal by consecutive laparoscopies at 1, 3, 6–7, 9–10, and 15–16 mo after inoculation. Following laparoscopy, matched eutopic and ectopic endometrium was harvested by laparotomy at each time point. In addition, both eutopic and ectopic tissues were also obtained from two baboons with spontaneous disease. The Animal Care Committee of the University of Illinois at Chicago approved all animal experiments.
The menstrual cycles of all animals were monitored by measuring serum estradiol [14] and the day of ovulation was determined based on the 17ß-estradiol (E2) surge. The day of the E2 surge was designated as Day –1; the luteinizing hormone surge followed 24 hours later, corresponding to the day of ovulation (Day 0). Tissues were harvested between Days 8 and 11 postovulation (PO), which corresponds to the approximate time of implantation in the baboon.
Tissue Samples
Endometrial tissues harvested at the time of laparotomy were either snap-frozen in liquid N2 for RNA extraction or fixed in 10% buffered formalin for immunohistochemistry. Endometriotic lesions for immunohistological analyses were fixed with a limited amount of surrounding tissue (i.e., fat, muscle, and peritoneum) to maintain orientation; lesions for RNA expression studies were dissected free of the surrounding tissue to avoid any contamination with nonendometrial tissue prior to snap-freezing in liquid N2. Control endometrium was similarly harvested from disease-free animals at Day 9–11 PO or during the late proliferative phase of the cycle. Menstrual endometrial tissue was collected at Day 2 postmenses using a Unimar pipelle (Cooper Surgical Inc.) and represents the shed functionalis from the previous cycle.
RNA Preparation, cDNA Synthesis, and Quantitative Real Time PCR
Frozen tissues were homogenized and RNA extracted using the Trizol reagent (Molecular Research Center) according to the manufacturer's protocol. RNA quality was determined by photometric analyses and by gel electrophoresis.
Following a DNase treatment (Invitrogen), reverse transcription reactions were carried out from 2 µg of total cellular RNA. Subsequent real-time PCR reactions were processed in triplicate using an ABI Prism 7700 Sequence Detector (Applied Biosystems) in a total volume of 25 µl containing 80 ng cDNA, gene-specific primers (for primers see Table 1), and Master Mix including SYBR Green reagent (Applied Biosystems). For the VEGF gene, we chose specific primers spanning the exon 1 and exon 2 boundary that recognize all splice variants of the vascular endothelial growth factor A gene. To determine the copy number of PCR fragments, serially diluted standard cDNAs generated from amplicons of CYR61, ß-actin (ACTB) and VEGF were used. Melting curve analysis allowed determination of specificity of the PCR fragments.
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Because of the diversity in the RNA quality, the quantification was performed by normalizing the expression levels of CYR61 and VEGF transcripts to the housekeeping gene ACTB.
Immunohistochemistry
Immunostaining of CYR61 was performed on 5-µm formalin-fixed paraffin-embedded sections applying the diaminobenzidine staining method with the VECTASTAIN Elite ABC kit (Vector Laboratories) according to the manufacturer's protocol. Endogenous peroxidase activity was inhibited by 0.3% H2O2. After blocking with 3% normal goat serum in TBS, rabbit anti-human CYR61 antibody (kindly provided by Dr. Lester F. Lau, University of Illinois, Chicago, IL) was used at a concentration of 11.4 µg/ml. The synthesis of the antibody and its specificity are described elsewhere [15]. In each immunohistochemical analysis a negative control was performed with purified rabbit IgGs as a substitute for the primary antibody, at the same concentration as the CYR61 antibody. Stained sections were examined on a Zeiss Axiophot microscope (Zeiss) and documented using a Nikon DS-U1 camera and LUCIA Image Analysis software (Nikon).
Statistical Analysis
Exploratory data analyses, Mann-Whitney test for the nonparametric independent two-group comparisons, and Spearman's correlation analyses were performed with the program SPSS 10 for Windows (SPSS Inc.). Differences with P 
0.05 were regarded as statistically significant.
RESULTS
CYR61 Expression in Cycling Endometrium
CYR61 mRNA was present in all the endometrial tissues from control animals, and the relative mRNA levels did not change significantly during the proliferative and secretory phases of the cycle (Fig. 1). However, in menstrual tissues, which are routinely used in our inoculation protocol [13], CYR61 mRNA showed a 7.3-fold increase in expression, which was significantly higher (P < 0.001) than that found in proliferative and secretory phase endometrium (Fig. 1).
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CYR61 protein was primarily immunolocalized to the epithelial cells of the endometrium (Fig. 2). In the proliferative phase, the CYR61 showed a diffuse distribution pattern in the glandular epithelial cells of the functionalis (Fig. 2, A and D), whereas the glands of the basalis expressed CYR61 at basal and apical portions (Fig. 2G). In the secretory phase, CYR61 was distinctly located at the luminal part of the glandular epithelium (Fig. 2, B and E). Menstrual endometrial tissue showed strong positive CYR61 staining with distinct epithelial distribution of the protein, as shown in Figure 2, C and F, corresponding to high CYR61 transcript levels in this tissue. Endothelia of small arterioles expressed CYR61 at all stages of the menstrual cycle. However, spiral arteries in secretory endometrium failed to stain for CYR61 (Fig. 2, B and H), whereas these vessels showed strong positive CYR61 staining both in the endothelia and in the muscle layer in menstrual endometrial tissue (Fig. 2, C, F, and I).
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CYR61 Expression in Endometriotic Endometrium
The expression of CYR61 mRNA was evaluated in the eutopic endometrium of six baboons with induced endometriosis at different time points of the disease as well as in two animals with spontaneously developed disease. The results were compared to cycle-matched control tissues from healthy baboons, which were harvested between Days 8 to 11 PO.
Transcript levels of CYR61 mRNA in eutopic endometrium were increased in animals with endometriosis as early as 1 mo postinoculation (Fig. 3A) with a mean increase of 4.0-fold (range from 1.7- to 6.0-fold) compared to the mean CYR61 transcript levels in cycle-matched control endometrium (n = 9). The maximal increase was found 3 mo after induction of endometriosis; this represented a mean 6.3-fold increase (range from 1.3- to 11.5-fold) in CYR61 mRNA expression when compared to the mean expression in cycle-matched control animals. However, this increase was not significantly different to the CYR61 expression level observed at 1 mo. The expression of CYR61 transcripts then decreased during progression of the disease, with a mean 3.0-fold upregulation 15 mo after induction of disease (n = 3, range from 0.1- to 8.6-fold). Two animals with spontaneously developed disease also showed an increased level of CYR61 mRNA when compared to cycle-matched eutopic endometrium from control animals (mean increase 2.0-fold; Fig. 3A). The mRNA expression analysis was further validated by the immunohistochemical data (Fig. 3, B–E). Compared to controls (Fig. 3B), eutopic endometrium obtained at 1 (Fig. 3C) and 3 mo postinoculation showed the most intense staining in both glandular and luminal epithelium. The staining intensity decreased as the disease progressed at 6 and 15 mo (Fig. 3, D and F), which also correlated with the quantitative PCR analysis.
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CYR61 Expression in Ectopic Endometrium
Upon induction of endometriosis, baboons develop several kinds of lesions, which adhere to multiple organs such as the peritoneum, uterus, bladder, and ovary. Detailed description of the lesions detected in baboons with induced endometriosis has been reported previously [12, 13]. The expression of CYR61 mRNA was analyzed in 28 lesions, including eight red, two yellow, five blue, four black, two white, and seven lesions of mixed pigmentation. The mean CYR61 mRNA expression in all ectopic lesions was 3-fold greater than that in matched eutopic endometriotic endometrium. Comparison with disease-free endometrium revealed an 11.7-fold increase in mean CYR61 mRNA expression in the uterus. The highest levels of CYR61 mRNA was observed in the highly vascularized red lesions, with a mean expression level of 18.46 (range from 0.96 to 41.26, n = 8), as illustrated in Figure 4A. White ectopic lesions, which are thought to represent less-active sites of disease, demonstrated the lowest levels of CYR61 transcripts, with a mean expression of 0.74 (0.46, 1.01, n = 2). Immunolocalization studies of CYR61 in the ectopic lesions showed that the protein was also primarily localized to the glandular epithelial cells within the lesion (Fig. 4B). In addition, the vascular endothelial cells also stained strongly for CYR61 (Fig. 4C).
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Correlation of CYR61 mRNA Expression to Expression of VEGF mRNA
Similar to CYR61, VEGF mRNA was significantly upregulated in the eutopic endometrium of baboons, with endometriosis between 8 and 11 days PO with a mean 4.4-fold increase compared to that measured in control, disease-free cycle matched eutopic endometrium (Fig. 5). In order to determine whether an association existed between CYR61 and VEGF mRNA expression, matched samples of eutopic and ectopic endometrium were compared (Fig. 5B). As with CYR61, the highest levels of VEGF transcripts were found in red lesions, as shown in Figure 5B. A strong positive correlation was demonstrated between CYR61 and VEGF mRNA expression in both ectopic endometriotic lesions and matched eutopic endometriotic endometrium (Spearman correlation, R = 0.87, P < 0.0001).
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DISCUSSION
The normal endometrium undergoes distinct morphological and functional changes that are a prerequisite for the establishment of pregnancy. Our extensive studies in the baboon have clearly established this nonhuman primate as an appropriate model to sequentially identify changes in the uterine endometrium associated with early implantation [16]. Furthermore, our more recent studies have also demonstrated that the induced model for endometriosis in the baboon results in changes in gene expression patterns in response to chorionic gonadotrophin stimulation [13]. Numerous studies have suggested that the proposed molecular markers of a receptive endometrium in women are aberrantly expressed in women with disease (reviewed in [17]). More recently, genome-wide microarray comparisons between women with or without endometriosis further validate the concept that endometrial gene expression within the window of uterine receptivity is altered [4, 18]. These abnormalities have been suggested to predispose these women to endometriosis. However, a problem with this assumption is the fact that the disease is already present, thus making it difficult to differentiate between cause and effect. In this study, we clearly demonstrate that the induction of the disease in a baboon model with no previous history of endometriosis alters the endometrial environment, suggesting that the presence of endometriotic lesions directly influences the endometrial environment. These alterations were further substantiated by comparing the CYR61 mRNA expression profile with baboons with spontaneous disease.
CYR61 is an estrogen-regulated gene that promotes cell adhesion, migration, and neovascularization (reviewed in [5]). CYR61 was identified as one of the most highly upregulated genes in the endometrium of women with endometriosis and was further upregulated in endometriotic lesions [4]. The studies reported herein confirm the human data and show for the first time that induction of the disease in a primate model results in deregulation of gene expression in the eutopic endometrium because of the presence of ectopic lesions. These results also provide evidence for a feedback mechanism from ectopic lesions to the eutopic endometrium, which can impair endometrial function.
We initially investigated the expression pattern of CYR61 transcripts in the endometrium of normally-cycling baboons. Unlike in the human endometrium, which expressed high CYR61 mRNA levels in the proliferative phase of the menstrual cycle [4], we found only moderate upregulation of CYR61 mRNA expression in proliferative endometrium of baboons compared to secretory endometrium. This may simply be a reflection of the small numbers of animals analyzed at this stage because of limited availability of tissues. Interestingly, CYR61 mRNA levels were significantly upregulated in endometrial tissues from menstruating baboons. This upregulation also occurs in women (unpublished results) and corresponds to the expression patterns of other angiogenic compounds in endometrium, such as VEGF and its receptors. Like CYR61, VEGF has been reported to be an estrogen-regulated gene in endometrium [19], and several studies have associated a higher level of VEGF, FLT1 (VEGFR1), and KDR (VEGFR2) mRNAs in human menstrual tissue when compared to endometrium obtained at other stages of the menstrual cycle [20, 21]. Because CYR61 mRNA was highly expressed in menstrual endometrial tissue, a question that needs to be addressed is whether CYR61 belongs to the family of genes induced by oxidative stress in endometrium, as has been shown for endometrial VEGF [22]. Previous studies have demonstrated that hypoxia-inducible factor-1 alpha (HIF1A) interacts with JUN and may thereby contribute to CYR61 transcriptional regulation under hypoxia in human melanoma cells [23]. In support of this, the transcription factor HIF1A has been shown to be highly upregulated in menstrual endometrium [24], and increased oxidative stress has been associated with higher prevalence to develop endometriosis [25]. Hence, CYR61 might function as a hypoxia-associated target gene to promote angiogenesis when retrograde menstrual tissue attaches to the peritoneum. Thus, menstrual endometrium, which is already rich in CYR61 and other angiogenic compounds, will have a greater propensity to stabilize capillary formation in an ectopic site. It is also conceivable that this tissue may adhere in the peritoneal cavity because of the adhesive and angiogenic properties of CYR61. Evidence for this possibility is further substantiated in our baboon model. Inoculation of menstrual tissue consistently results in the development of endometriotic lesions as early as 1 mo postinoculation [12, 13]. CYR61, which is aberrantly expressed in endometriotic eutopic endometrium during the window of receptivity, is an estrogen-regulated gene in both rodent and human endometrium [4, 26]. In addition to CYR61, our data also indicate that other estrogen-regulated genes such as FOS (c-fos) are also aberrantly regulated (unpublished results), suggesting that secretory-phase eutopic endometrium in women and baboons with endometriosis responds inadequately to progesterone. It has been suggested that either an aberrant expression of aromatase [13] or an imbalance in 17ß-hydroxysteroid dehydrogenases 1 and 2 [4, 27] may account for the upregulation of estrogen-dependent genes during the secretory phase. However, we saw a significant increase in CYR61 mRNA as early as 1 and 3 mo following the establishment of the disease. This is much earlier than the time point at which aromatase activity is detectable in both the ectopic and eutopic tissues in the baboon [13]. However, the paracrine mechanism directing the increase of CYR61 mRNA in the eutopic endometrium upon development of endometriotic lesions remains to be explored. Several other mediators have been suggested to be responsible for regulating CYR61 mRNA expression. Inflammatory cytokines such as interleukins, particularly IL6 and IL10, have been described to be amplified in peritoneal fluid and/or sera of patients with endometriosis [28, 29] and are likely candidates. Some interleukins, such as IL1ß, IL2, and IL6 are also known to induce CYR61 mRNA in vitro in an immediate early response manner [7].
The ectopic endometrium showed a different CYR61 mRNA expression pattern depending on lesion type, with maximal levels found in red lesions. Several studies have reported that red lesions are more vascularized, contain more immature vessels, and express higher levels of VEGF mRNA than other types of lesions [30–32]. Moreover, we found a positive correlation of CYR61 mRNA expression to VEGF transcripts in eutopic and all types of ectopic endometria, indicating a common regulation of both genes. The level of vascularization in ectopic endometrium depends on the lesion type, suggesting that the higher amount of CYR61 mRNA in the more highly vascularized red lesions may be a result of increased numbers of endothelial cells expressing CYR61 mRNA. Further investigations are needed to clarify whether CYR61 could play a role in vessel maturation mediated by recruitment of pericytes. It has also been suggested that the establishment and development of endometriosis are associated with increased VEGF mRNA expression caused by hypoxic stress [22]. The fact that menstrual tissue, which serves as our inoculation material, expresses high levels of both CYR61 and VEGF transcripts would support the hypothesis that these two proangiogenic factors play a critical role in enabling the menstrual tissue to attach and grow at an ectopic site. An alternative mechanism as to how CYR61 affects the pathogenesis of endometriosis is also possible.
The proangiogenic function of endometriotic CYR61 may be mediated by integrins, such as ITGAV, ITGA6, ITGB1, and ITGB3, which have been already shown to play a role in human CYR61-mediated adhesion and angiogenesis (reviewed in [33]). These integrins are expressed in human endometrium and, moreover, ITGAV and ITGB3 are even upregulated in endometriotic lesions [34–36]. By binding to integrins, CYR61 interacts with numerous other proteins, such as NFKB1, BIRC4, and MAPK3/MAPK1, and induces signal cascades, which may contribute to the establishment and development of endometriotic lesions. Those possibilities are currently under investigation.
The exact mechanisms by which CYR61 mediates the pathogenesis of endometriosis remain to be fully elucidated. What is evident, however, is that, as in human, CYR61 mRNA expression is upregulated in both the eutopic and ectopic endometrium of baboons experimentally induced with endometriosis; this upregulation is presumably a consequence of induced disease. This implies a powerful feedback mechanism from the early lesions to alter eutopic endometrial function and maintain the secretory endometrium in an estrogenic state, which in turn would be detrimental to the establishment of pregnancy.
Furthermore, the abundant expression of CYR61 transcripts in baboons with induced disease may facilitate the establishment of lesions in an ectopic side. This could contribute to the chronic persistence of endometriosis in both human and nonhuman primates.
ACKNOWLEDGMENTS
The authors thank Toyin Knight, Xuimei Jeng, and Daniela Kottmann for their excellent technical assistance. We are grateful to Dr. L.F. Lau at Department of Biochemistry and Molecular Genetics, University Of Illinois at Chicago, for the generous gift of the CYR61 antibody.
FOOTNOTES
1 Supported by a fellowship within the Postdoc Program of the German Academic Exchange Service (DAAD) to I.G. and NICHD U54 HD40093 to A.T.F. 
2 Correspondence. FAX: 49 201 723 5619; isabella.gashaw{at}uni-essen.de
Received: 16 November 2005.
First decision: 17 December 2005.
Accepted: 14 February 2006.
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