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• W2019014038 abstract "Endometriosis is a common gynecological disease that affects approximately 10% of women of childbearing age. It is characterized by endometrial growth outside the uterus and often results in inflamed lesions, pain, and reduced fertility. Although heightened estrogenic activity and/or reduced progesterone responsiveness are considered to be involved in the etiology of endometriosis, neither the extent of their participation nor the underlying mechanisms are clearly understood. Heterogeneous uterine cell types differentially respond to estrogen and progesterone (P4). P4, primarily acting via its nuclear receptor (PR), activates gene transcription and impacts many reproductive processes. Deletion of Fkbp52, an immunophilin cochaperone for PR, results in uterine-specific P4 resistance in mice, creating an opportunity to study the unique aspects of P4 signaling in endometriosis. Here we explored the roles of FKBP52 in this disease using Fkbp52−/− mice. We found that the loss of FKBP52 encourages the growth of endometriotic lesions with increased inflammation, cell proliferation, and angiogenesis. We also found remarkable down-regulation of FKBP52 in cases of human endometriosis. Our results provide the first evidence corroborated by genetic studies in mice for a potential role of an immunophilin cochaperone in the etiology of human endometriosis. This investigation is highly relevant for clinical application, particularly because P4 resistance is favorably indicated in endometriosis and other gynecological diseases. Endometriosis is a common gynecological disease that affects approximately 10% of women of childbearing age. It is characterized by endometrial growth outside the uterus and often results in inflamed lesions, pain, and reduced fertility. Although heightened estrogenic activity and/or reduced progesterone responsiveness are considered to be involved in the etiology of endometriosis, neither the extent of their participation nor the underlying mechanisms are clearly understood. Heterogeneous uterine cell types differentially respond to estrogen and progesterone (P4). P4, primarily acting via its nuclear receptor (PR), activates gene transcription and impacts many reproductive processes. Deletion of Fkbp52, an immunophilin cochaperone for PR, results in uterine-specific P4 resistance in mice, creating an opportunity to study the unique aspects of P4 signaling in endometriosis. Here we explored the roles of FKBP52 in this disease using Fkbp52−/− mice. We found that the loss of FKBP52 encourages the growth of endometriotic lesions with increased inflammation, cell proliferation, and angiogenesis. We also found remarkable down-regulation of FKBP52 in cases of human endometriosis. Our results provide the first evidence corroborated by genetic studies in mice for a potential role of an immunophilin cochaperone in the etiology of human endometriosis. This investigation is highly relevant for clinical application, particularly because P4 resistance is favorably indicated in endometriosis and other gynecological diseases. Endometriosis, the growth of endometrium-like tissues outside the uterus that differentially respond to reproductive hormones, is a common gynecological disease often associated with pelvic pain and infertility, affecting about 10% of women of reproductive age.1Maruyama M Osuga Y Momoeda M Yano T Tsutsumi O Taketani Y Pregnancy rates after laparoscopic treatment. Differences related to tubal status and presence of endometriosis.J Reprod Med. 2000; 45: 89-93PubMed Google Scholar, 2Momoeda M Taketani Y Terakawa N Hoshiai H Tanaka K Tsutsumi O Osuga Y Maruyama M Harada T Obata K Hayashi K Is endometriosis really associated with pain?.Gynecol Obstet Invest. 2002; 54 (discussion 21–13): 18-21Crossref PubMed Scopus (34) Google Scholar, 3Giudice LC Kao LC Endometriosis.Lancet. 2004; 364: 1789-1799Abstract Full Text Full Text PDF PubMed Scopus (2561) Google Scholar Although the etiology of endometriosis remains elusive, implantation and growth of endometrial tissues within the peritoneal cavity after retrograde menstruation is a widely accepted pathogenesis.4Sampson JA Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the pelvic cavity.Am J Obstet Gynecol. 1927; 14: 422-469Abstract Full Text PDF Google Scholar Estrogen, a potent mitogen that affects both eutopic endometria and ectopic lesions, is thought to be a major player in the development of endometriosis.5Kitawaki J Kado N Ishihara H Koshiba H Kitaoka Y Honjo H Endometriosis: the pathophysiology as an estrogen-dependent disease.J Steroid Biochem Mol Biol. 2002; 83: 149-155Crossref PubMed Scopus (287) Google Scholar The basis of this tenet is that endometriotic lesions regress in low-estrogen environments, eg, in menopausal women, in patients after ovariectomy or in women undergoing hormonal therapy with gonadotropin-releasing hormone agonists.6Lessey BA Medical management of endometriosis and infertility.Fertil Steril. 2000; 73: 1089-1096Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar Progesterone (P4) is also considered an important contributor to this disease, because it inhibits the mitogenic action of estrogen and promotes endometrial cell differentiation.7Lydon JP DeMayo FJ Funk CR Mani SK Hughes AR Montgomery Jr, CA Shyamala G Conneely OM O'Malley BW Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.Genes Dev. 1995; 9: 2266-2278Crossref PubMed Scopus (1522) Google Scholar Regression of endometriosis often occurs in women under high progesterone dominance, ie, during pregnancy or those undergoing progestogen therapy.6Lessey BA Medical management of endometriosis and infertility.Fertil Steril. 2000; 73: 1089-1096Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar There is also evidence that endometriosis is aggravated in PR−/− mice8Fang Z Yang S Lydon JP DeMayo F Tamura M Gurates B Bulun SE Intact progesterone receptors are essential to counteract the proliferative effect of estradiol in a genetically engineered mouse model of endometriosis.Fertil Steril. 2004; 82: 673-678Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar and that P4 responsiveness in eutopic and ectopic endometria is reduced compared to disease-free endometria in humans.9Bruner-Tran KL Eisenberg E Yeaman GR Anderson TA McBean J Osteen KG Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice.J Clin Endocrinol Metab. 2002; 87: 4782-4791Crossref PubMed Scopus (162) Google Scholar, 10Minici F Tiberi F Tropea A Orlando M Gangale MF Romani F Campo S Bompiani A Lanzone A Apa R Endometriosis and human infertility: a new investigation into the role of eutopic endometrium.Hum Reprod. 2008; 23: 530-537Crossref PubMed Scopus (70) Google Scholar Furthermore, progesterone receptor (PR) expression and the antiproliferative effects imposed by P4-PR signaling are suppressed in endometriosis.11Attia GR Zeitoun K Edwards D Johns A Carr BR Bulun SE Progesterone receptor isoform A but not B is expressed in endometriosis.J Clin Endocrinol Metab. 2000; 85: 2897-2902Crossref PubMed Scopus (422) Google Scholar, 12Bulun SE Cheng YH Yin P Imir G Utsunomiya H Attar E Innes J Kim Julie J Progesterone resistance in endometriosis: link to failure to metabolize estradiol.Mol Cell Endocrinol. 2006; 248: 94-103Crossref PubMed Scopus (313) Google Scholar In addition, many P4-responsive genes are aberrantly expressed in eutopic endometria of women with endometriosis.13Kao LC Germeyer A Tulac S Lobo S Yang JP Taylor RN Osteen K Lessey BA Giudice LC Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility.Endocrinology. 2003; 144: 2870-2881Crossref PubMed Scopus (599) Google Scholar, 14Burney RO Talbi S Hamilton AE Vo KC Nyegaard M Nezhat CR Lessey BA Giudice LC Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis.Endocrinology. 2007; 148: 3814-3826Crossref PubMed Scopus (576) Google Scholar However, clinical studies have shown that endometriosis-related pain in select patients is sustained despite progestin therapy.3Giudice LC Kao LC Endometriosis.Lancet. 2004; 364: 1789-1799Abstract Full Text Full Text PDF PubMed Scopus (2561) Google Scholar, 6Lessey BA Medical management of endometriosis and infertility.Fertil Steril. 2000; 73: 1089-1096Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar The prevailing hypothesis is that an enhanced estrogenic influence and/or reduced P4 responsiveness leads to endometriosis.3Giudice LC Kao LC Endometriosis.Lancet. 2004; 364: 1789-1799Abstract Full Text Full Text PDF PubMed Scopus (2561) Google Scholar, 12Bulun SE Cheng YH Yin P Imir G Utsunomiya H Attar E Innes J Kim Julie J Progesterone resistance in endometriosis: link to failure to metabolize estradiol.Mol Cell Endocrinol. 2006; 248: 94-103Crossref PubMed Scopus (313) Google Scholar, 14Burney RO Talbi S Hamilton AE Vo KC Nyegaard M Nezhat CR Lessey BA Giudice LC Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis.Endocrinology. 2007; 148: 3814-3826Crossref PubMed Scopus (576) Google Scholar Therefore, an animal model presenting more than normal estrogenic activity with suboptimal P4 responsiveness will be valuable for delineating the etiology of endometriosis, because all human studies focus on this disease when it is already in progress or established, precluding studies on its initiation. Mice missing FKBP52 fulfill this purpose, because these null females show uterine specific P4 resistance as described below. The immunophilin cochaperone FK506-binding protein 4 (FKBP52) is a key component of the mature PR complex. Functionally mature steroid hormone receptors including that of PR consist of a receptor monomer, a 90-kDa heat shock protein (Hsp90) dimer, the cochaperone p23, and one of the four cochaperones containing a tetratricopeptide repeat that binds to Hsp90.15Barent RL Nair SC Carr DC Ruan Y Rimerman RA Fulton J Zhang Y Smith DF Analysis of FKBP51/FKBP52 chimeras and mutants for Hsp90 binding and association with progesterone receptor complexes.Mol Endocrinol. 1998; 12: 342-354Crossref PubMed Google Scholar FKBP52 is one such cochaperone that binds both Hsp90 and PR to stabilize the complex for optimal P4 binding to PR and subsequent transcriptional activation.15Barent RL Nair SC Carr DC Ruan Y Rimerman RA Fulton J Zhang Y Smith DF Analysis of FKBP51/FKBP52 chimeras and mutants for Hsp90 binding and association with progesterone receptor complexes.Mol Endocrinol. 1998; 12: 342-354Crossref PubMed Google Scholar Basal PR responsiveness, however, persists in the absence of FKBP52.16Tranguch S Cheung-Flynn J Daikoku T Prapapanich V Cox MB Xie H Wang H Das SK Smith DF Dey SK Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation.Proc Natl Acad Sci USA. 2005; 102: 14326-14331Crossref PubMed Scopus (198) Google Scholar We have recently shown that Fkbp52 deficient female mice with normal PR expression and P4 levels show reduced uterine PR responsiveness with more than normal estrogenic influence, leading to implantation failure.16Tranguch S Cheung-Flynn J Daikoku T Prapapanich V Cox MB Xie H Wang H Das SK Smith DF Dey SK Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation.Proc Natl Acad Sci USA. 2005; 102: 14326-14331Crossref PubMed Scopus (198) Google Scholar Implantation and full-term pregnancy, however, can be rescued with excess P4 supplementation, depending on the genetic background of mice.17Tranguch S Wang H Daikoku T Xie H Smith DF Dey SK FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific.J Clin Invest. 2007; 117: 1824-1834Crossref PubMed Scopus (103) Google Scholar Thus, FKBP52 deficiency confers endometrial P4 resistance during pregnancy. Because serum ovarian hormone levels during the menstrual cycle in women with endometriosis are similar to those without endometriosis, it is possible that reduced P4-PR signaling, rather than reduced P4 levels, is a major contributing factor for P4 resistance in endometriosis. Unlike PR−/− mice with no P4-PR signaling, Fkbp52−/− mice with basal uterine P4-PR responsiveness are perhaps a more physiologically relevant model to study the role of P4 resistance in endometriosis.16Tranguch S Cheung-Flynn J Daikoku T Prapapanich V Cox MB Xie H Wang H Das SK Smith DF Dey SK Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation.Proc Natl Acad Sci USA. 2005; 102: 14326-14331Crossref PubMed Scopus (198) Google Scholar Using Fkbp52−/− females, we show here that FKBP52 deficiency promotes the growth of endometriotic lesions with increased inflammation, cell proliferation and angiogenesis. These findings in mice corroborate our observations of down-regulation of FKBP52 expression in eutopic endometria and ectopic lesions of women with endometriosis compared to endometria of women without endometriosis. Together, these findings provide evidence that reduced levels of FKBP52 contribute to decreased P4 responsiveness in furthering the development of endometriosis. Fkbp52 null mice were originally established on a C57BL/6/129SvJ background18Cheung-Flynn J Prapapanich V Cox MB Riggs DL Suarez-Quian C Smith DF Physiological role for the cochaperone FKBP52 in androgen receptor signaling.Mol Endocrinol. 2005; 19: 1654-1666Crossref PubMed Scopus (170) Google Scholar and then backcrossed with CD1 mice to the F10 generation.17Tranguch S Wang H Daikoku T Xie H Smith DF Dey SK FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific.J Clin Invest. 2007; 117: 1824-1834Crossref PubMed Scopus (103) Google Scholar Flk1lacZ+/− transgenic mice were originally generated on a C57BL/6J/Sv129 background and backcrossed to CD1 background to the F10 generation.19Wang H Xie H Sun X Tranguch S Zhang H Jia X Wang D Das SK Desvergne B Wahli W DuBois RN Dey SK Stage-specific integration of maternal and embryonic peroxisome proliferator-activated receptor delta signaling is critical to pregnancy success.J Biol Chem. 2007; 282: 37770-37782Crossref PubMed Scopus (53) Google Scholar CD1 Fkbp52−/−/Flk1lacZ+/− (knockout [KO]; FlkKO) mice were generated by crossing Fkbp52+/−/Flk1lacZ+/− males and Fkbp52+/− females. Fkbp52+/+/Flk1lacZ+/− (wild-type [WT]; Flk1WT) littermates were used as control. Mice were housed and used in the present investigation in accordance with the National Institutes of Health and institutional guidelines on the care and use of laboratory animals. There is evidence that estrogen promotes growth of endometriotic lesions in ovariectomized mice.20Hirata T Osuga Y Yoshino O Hirota Y Harada M Takemura Y Morimoto C Koga K Yano T Tsutsumi O Taketani Y Development of an experimental model of endometriosis using mice that ubiquitously express green fluorescent protein.Hum Reprod. 2005; 20: 2092-2096Crossref PubMed Scopus (75) Google Scholar However, estrogen doses used in the study were much higher than physiological levels. Fkbp52 null mice have normal estrous cycles and the status of ovarian hormones during early pregnancy is comparable to WT littermates (data not shown). Because we have shown that Fkbp52−/− uteri during pregnancy have more than normal estrogenic influence due to uterine P4 resistance,17Tranguch S Wang H Daikoku T Xie H Smith DF Dey SK FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific.J Clin Invest. 2007; 117: 1824-1834Crossref PubMed Scopus (103) Google Scholar we were able to circumvent ovariectomy or estrogen treatment in our current study of endometriosis. Induction of endometriosis was performed according to the method previously published with some modifications.20Hirata T Osuga Y Yoshino O Hirota Y Harada M Takemura Y Morimoto C Koga K Yano T Tsutsumi O Taketani Y Development of an experimental model of endometriosis using mice that ubiquitously express green fluorescent protein.Hum Reprod. 2005; 20: 2092-2096Crossref PubMed Scopus (75) Google Scholar, 21Yoshino O Osuga Y Koga K Hirota Y Hirata T Ruimeng X Na L Yano T Tsutsumi O Taketani Y FR 167653, a p38 mitogen-activated protein kinase inhibitor, suppresses the development of endometriosis in a murine model.J Reprod Immunol. 2006; 72: 85-93Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Seven to ten-week-old female mice were used for endometriosis induction. Vaginal smears of all mice were examined daily at least 7 days before inoculation. Mice in diestrus were selected to be used for donor and recipient mice. Donor mice were sacrificed, and 0.8 ml PBS was injected into the peritoneal cavity, and peritoneal fluid (donor/control) was collected. Then, uterine horns were removed and weighed. One piece of uterine tissue was kept in 10% neutral-buffered formalin as a control (donor) for immunostaining. The remaining uterine tissue was placed into a dish and minced using a surgical knife. Fragments suspended in 0.6 ml PBS were injected with an 18-gauge needle through the abdominal wall just below the umbilicus into the peritoneal cavity of recipient mice with the ratio of 1 donor to 2 recipients. All procedures were performed under aseptic conditions. Fourteen days postinjection, recipient mice were sacrificed, their peritoneal cavities washed with 0.8 ml PBS, and peritoneal fluid collected. Then, uteri (eutopic) and endometriotic implants (ectopic) were removed and weighed. Tissues were fixed in 10% neutral-buffered formalin for histological analysis and immunostaining, or in 0.2% paraformaldehyde solution for lacZ staining. Each sample of peritoneal fluid was centrifuged, and the supernatant was kept at −80°C until enzyme-linked immunosorbent assay. The following tissues were obtained from 80 women undergoing laparoscopy: 1) endometrial tissues of women without endometriosis (endometriosis-free endometrium, n = 40), 2) endometrial tissues of women with endometriosis (eutopic endometrium, n = 40), 3) endometriotic tissues of women with endometriosis (ectopic endometrium; ovarian endometriosis, n = 32: peritoneal endometriosis, n = 8: deep-infiltrating endometriosis, n = 4). All women underwent laparoscopy for pain, infertility or other benign gynecological disorders during the period of 2006 to 2007. Endometriosis was diagnosed laparoscopically and confirmed histologically. Lesions of deep-infiltrating endometriosis were defined as those deeper than 5 mm beneath the peritoneal surface according to the previous study by Cornillie et al.22Cornillie FJ Oosterlynck D Lauweryns JM Koninckx PR Deeply infiltrating pelvic endometriosis: histology and clinical significance.Fertil Steril. 1990; 53: 978-983Abstract Full Text PDF PubMed Scopus (501) Google Scholar Forty women (aged 35.8 ± 6.2 years; mean ± SD) were diagnosed with endometriosis, and 40 women (aged 37.2 ± 6.5 years) had no endometriosis. Severity of endometriosis was determined according to the revised American Society for Reproductive Medicine classification. Among 40 women with endometriosis, 17 and 23 women were classified as stage 3 and stage 4, respectively. Forty endometriosis-free endometria and 40 eutopic endometria were collected from 40 different women without and with endometriosis, respectively. Eight of 44 endometriotic lesions were obtained simultaneously from four women, and rest of them from 36 different individuals. All subjects had regular menstrual cycles without any hormonal treatment for at least 6 months before surgery. Endometrial samples were dated according to the women's menstrual history and standard histological criteria by Noyes et al.23Noyes RW Hertig AI Rock J Dating the endometrial biopsy.Fertil Steril. 1950; 1: 3-25Crossref Google Scholar Tissues were fixed for histology and immunohistochemistry and snap-frozen for RNA isolation. The experimental procedures were approved by the institutional review board of University of Tokyo (IRB number 324), and signed informed consent for use of tissues was obtained from each woman. Immunostaining of Ki-67, cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), PR, FKBP52, and estrogen receptor (ER) α was performed in 10% neutral-buffered formalin-fixed and paraffin-embedded sections (5 μm) of human and mouse tissues as previously described.24Daikoku T Tranguch S Friedman DB Das SK Smith DF Dey SK Proteomic analysis identifies immunophilin FK506 binding protein 4 (FKBP52) as a downstream target of Hoxa10 in the periimplantation mouse uterus.Mol Endocrinol. 2005; 19: 683-697Crossref PubMed Scopus (79) Google Scholar Antibodies specific to Ki-67 (Thermo Fisher Scientific, Fremont, CA), COX-2 (Cayman Chemical, Ann Arbor, MI), VEGF (Santa Cruz Biotechnology, Santa Cruz, CA), PR (Zymed Laboratories, Carlsbad, CA), FKBP52 (kindly given by David F Smith, Mayo Clinic), and ERα (Santa Cruz Biotechnology) were used. A Histostain-Plus kit (Zymed Laboratories) was used to visualize specific antigens. Brown deposits indicate sites of positive immunostaining. Aberrant proliferation in ectopic lesions is a characteristic of endometriosis, with ectopic cells growing outside the normal hormonal regulation. In fact, the pattern of cell proliferation in ectopic lesions differs from estrogen- and P4-governed proliferation of eutopic endometria.25Nisolle M Casanas-Roux F Donnez J Immunohistochemical analysis of proliferative activity and steroid receptor expression in peritoneal and ovarian endometriosis.Fertil Steril. 1997; 68: 912-919Abstract Full Text PDF PubMed Scopus (127) Google Scholar, 26Beliard A Noel A Foidart JM Reduction of apoptosis and proliferation in endometriosis.Fertil Steril. 2004; 82: 80-85Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar The proliferative status of mouse ectopic lesions due to FKBP52 deficiency was assessed by Ki-67 immunohistochemistry. For Ki-67 quantification, five high-powered fields per respective section were analyzed microscopically. The percentage of the total cells staining for Ki-67 was calculated. COX-2 and VEGF are widely accepted markers of endometriosis and are associated with its pathophysiology.27Sales KJ Jabbour HN Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium.Reproduction. 2003; 126: 559-567Crossref PubMed Scopus (134) Google Scholar, 28McLaren J Vascular endothelial growth factor and endometriotic angiogenesis.Hum Reprod Update. 2000; 6: 45-55Crossref PubMed Scopus (227) Google Scholar To assess whether there is any similarity between our mouse model of endometriosis with that of humans, immunostaining of COX-2 and VEGF was performed in uterine sections from donors (controls), as well as in sections from eutopic endometria and ectopic lesions retrieved from reciprocal transplantation of endometrial tissue in mice. Estrogen is a key factor in development of endometriosis, and the levels of ER and PR expression modulate estrogenic effects on various cells and tissues. To evaluate the contribution of these hormone receptors to our mouse model of endometriosis, immunostaining of PR and ERα was also performed. In addition, immunostaining of COX-2, VEGF, and PR in human endometriosis was performed to compare with the results of those in our mouse model of endometriosis. FKBP52 immunostaining was performed in both human and mouse tissues. The intensity of staining was analyzed by a semiquantitative method, H-scoring.29McCarty Jr, KS Miller LS Cox EB Konrath J McCarty Sr, KS Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies.Arch Pathol Lab Med. 1985; 109: 716-721PubMed Google Scholar H-score was calculated by the following equation: H-score = ∑Pi(i + 1) where i is the intensity of staining with a value of 0, 1, 2, or 3 (negative, weak, moderate, or strong, respectively) and Pi is the corresponding percentage of the cells. Five high-powered fields per respective section were analyzed microscopically. Stromal cells in mice and both epithelial and stromal cells in humans were evaluated. LacZ staining and quantification of vessel density were performed as previously described.30Ma W Tan J Matsumoto H Robert B Abrahamson DR Das SK Dey SK Adult tissue angiogenesis: evidence for negative regulation by estrogen in the uterus.Mol Endocrinol. 2001; 15: 1983-1992Crossref PubMed Scopus (97) Google Scholar, 31Matsumoto H Ma WG Daikoku T Zhao X Paria BC Das SK Trzaskos JM Dey SK Cyclooxygenase-2 differentially directs uterine angiogenesis during implantation in mice.J Biol Chem. 2002; 277: 29260-29267Crossref PubMed Scopus (142) Google Scholar Briefly, tissues were fixed in 0.2% paraformaldehyde for 24 hours followed by infusion in 30% sucrose at 4°C overnight. Tissues were then embedded in optimal cutting temperature compound and snap-frozen. Frozen sections were mounted onto glass slides and stained overnight at 37°C using β-galactosidase as a substrate. Sections were counterstained with eosin. Blue deposits indicate sites of positive staining. Endometriotic lesion areas occupied by lacZ-stained blood vessels were quantified. Six sections per lesion were randomly selected, digital images were obtained, and measurements were made using the Scion Image (Scion Corporation, Frederick, MD). The percentage of area occupied by lacZ-positive vessels was measured for each section. There is evidence that several cytokines and growth factors are increased in peritoneal fluids of women with endometriosis and associated with its pathophysiology.32Gazvani R Templeton A Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis.Reproduction. 2002; 123: 217-226Crossref PubMed Scopus (312) Google Scholar, 33Oral E Olive DL Arici A The peritoneal environment in endometriosis.Hum Reprod Update. 1996; 2: 385-398Crossref PubMed Scopus (171) Google Scholar Among the up-regulated factors, levels of monocyte chemotactic protein-1 (MCP-1), regulated on activation, normal T-cell expressed and secreted (RANTES) and VEGF are elevated by estrogen.34Akoum A Jolicoeur C Boucher A Estradiol amplifies interleukin-1-induced monocyte chemotactic protein-1 expression by ectopic endometrial cells of women with endometriosis.J Clin Endocrinol Metab. 2000; 85: 896-904Crossref PubMed Scopus (83) Google Scholar, 35Akoum A Lemay A Maheux R Estradiol and interleukin-1beta exert a synergistic stimulatory effect on the expression of the chemokine regulated upon activation, normal T cell expressed, and secreted in endometriotic cells.J Clin Endocrinol Metab. 2002; 87: 5785-5792Crossref PubMed Scopus (66) Google Scholar, 36Shifren JL Tseng JF Zaloudek CJ Ryan IP Meng YG Ferrara N Jaffe RB Taylor RN Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis.J Clin Endocrinol Metab. 1996; 81: 3112-3118Crossref PubMed Scopus (631) Google Scholar, 37McLaren J Prentice A Charnock-Jones DS Millican SA Muller KH Sharkey AM Smith SK Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids.J Clin Invest. 1996; 98: 482-489Crossref PubMed Scopus (442) Google Scholar To assess the contribution of FKBP52 deficiency to excessive estrogenic effects, concentrations of MCP-1, RANTES, and VEGF in mouse peritoneal fluid were measured by respective enzyme-linked immunosorbent assay kits (R&D systems, Minneapolis, MN) according to the manufacturer's protocol. Absorbance was read at 450 nm with an ELx800 automated microplate reader (BIO-TEK, Winooski, VT). Total RNA was isolated from human tissues using Isogen (Nippongene, Toyama, Japan). Reverse transcription (RT) and quantitative PCR were performed as previously described.38Hirota Y Osuga Y Koga K Yoshino O Hirata T Morimoto C Harada M Takemura Y Nose E Yano T Tsutsumi O Taketani Y The expression and possible roles of chemokine CXCL11 and its receptor CXCR3 in the human endometrium.J Immunol. 2006; 177: 8813-8821PubMed Google Scholar The RT reaction was performed using ReverTra Ace-α (Toyobo, Osaka, Japan). Quantitative PCR was performed in a LightCycler (Roche Diagnostics GmbH, Mannheim, Germany) using FastStart DNA Master Plus SYBR Green (Roche Diagnostics GmbH). The following primers were used: Fkbp52, sense, 5′-AGATGACAGCCGAGGAGATG-3′; antisense, 5′-AATTTGTCCTTGCGATCCAG-3′; Gapdh, sense, 5′-ACCACAGTCCATGCCATCAC-3′, antisense, 5′-TCCACCACCCTGTTGCTGTA-3′. Fkbp52 expression was normalized to RNA loading for each sample using Gapdh mRNA as an internal standard. Standardization of data was performed by subtracting the signal threshold cycles of Gapdh from that of Fkbp52. Each PCR product was purified with a QIAEX II gel extraction kit (Qiagen, Hilden, Germany), and identities were confirmed using an ABI PRISM 310 genetic analyzer (Applied Biosystems, Foster City, CA). Mann-Whitney U-test was used to compare expression levels of Fkbp52 mRNA in human tissues. All other data were analyzed using unpaired Student's t-test and analysis of variance with posthoc analysis. P < 0.05 was accepted as statistically significant. Using Fkbp52−/− mice, we examined the effects of FKBP52 deficiency on endometriosis and the relative roles of donor versus recipient FKBP52 in this disease using reciprocal transplantation of endometrial tissue minces within the peritoneum. All donor and recipient mice were synchronized at the diestrus stage to have their hormonal milieu comparable. Our" @default.
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• W2019014038 date "2008-12-01" @default.
• W2019014038 modified "2023-10-03" @default.
• W2019014038 title "Deficiency of Immunophilin FKBP52 Promotes Endometriosis" @default.
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• W2019014038 doi "https://doi.org/10.2353/ajpath.2008.080527" @default.
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