Increased immunoreactivity to SLIT/ROBO1 and its correlation with severity of dysmenorrhea in adenomyosis

Nie, Jichan; Liu, Xishi; Zheng, Yu; Geng, Jian Guo; Guo, Sun Wei

doi:10.1016/j.fertnstert.2010.09.027

Cited by 24 publications

(22 citation statements)

References 24 publications

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“…In nine articles, vascular characteristics or the MVD in endometrium of patients with adenomyosis was studied by quantification of microvessels through either CD31, CD34, von Willebrand Factor (vWF) or factor VIII (FVIII) antibody staining (Liu et al ., 2016; Wang et al ., 2016; Nie et al ., 2011; Tokyol et al ., 2009; Huang et al ., 2014; Li et al ., 2006; Schindl et al ., 2001; Nie and Liu, 2016; Ota et al ., 1998). Staining of these markers exclusively occurs in endothelial cells of blood vessels (Table III).…”

Section: Resultsmentioning

confidence: 99%

“…In all articles that assessed the ectopic endometrium, the MVD was significantly increased compared with the control endometrium. Six studies found a significantly increased MVD in the eutopic endometrium from adenomyosis patients compared with the control endometrium (Liu et al ., 2016; Huang et al ., 2014; Wang et al ., 2016; Nie et al ., 2011; Ota et al ., 1998; Nie and Liu, 2016), while two studies reported no significant difference (Schindl et al ., 2001; Tokyol et al ., 2009), and one did not study the difference between eutopic endometrium and control endometrium (Liu et al ., 2016).…”

Section: Resultsmentioning

confidence: 99%

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Role of angiogenesis in adenomyosis-associated abnormal uterine bleeding and subfertility: a systematic review

Harmsen

Wong

Mijatovic

et al. 2019

Human Reproduction Update

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BackgroundAdenomyosis commonly occurs with abnormal uterine bleeding (AUB) and is associated with subfertility and a higher miscarriage rate. Recent evidence showed abnormal vascularization in the endometrium in patients with adenomyosis, suggesting a role of angiogenesis in the pathophysiology of AUB and subfertility in adenomyosis and providing a possible treatment target.Objective and rationaleWe hypothesized that the level of abnormal vascularization and expression of angiogenic markers is increased in the ectopic and eutopic endometrium of adenomyosis patients in comparison with the endometrium of control patients. This was investigated through a search of the literature.Search methodsA systematic search was performed in PubMed and Embase until February 2019. Combinations of terms for angiogenesis and adenomyosis were applied as well as AUB, subfertility or anti-angiogenic therapy. The main search was limited to clinical studies carried out on premenopausal women. Original research articles focusing on markers of angiogenesis in the endometrium of patients with adenomyosis were included. Studies in which no comparison was made to control patients or which were not published in a peer-reviewed journal were excluded. A second search was performed to explore the therapeutic potential of targeting angiogenesis in adenomyosis. This search also included preclinical studies.OutcomesA total of 20 articles out of 1669 hits met our selection criteria. The mean vascular density (MVD) was studied by quantification of CD31, CD34, von Willebrand Factor (vWF) or factor-VIII-antibody-stained microvessels in seven studies. All these studies reported a significantly increased MVD in ectopic endometrium, and out of the six articles that took it into account, four studies reported a significantly increased MVD in eutopic endometrium compared with control endometrium. Five articles showed a significantly higher vascular endothelial growth factor expression in ectopic endometrium and three articles in eutopic endometrium compared with control endometrium. The vascular and pro-angiogenic markers α-smooth muscle actin, endoglin, S100A13, vimentin, matrix metalloproteinases (MMPs), nuclear factor (NF)-kB, tissue factor (TF), DJ-1, phosphorylated mammalian target of rapamycin, activin A, folli- and myostatin, CD41, SLIT, roundabout 1 (ROBO1), cyclooxygenase-2, lysophosphatidic acid (LPA) 1,4-5, phospho signal transducer and activator of transcription 3 (pSTAT3), interleukin (IL)-6, IL-22 and transforming growth factor-β1 were increased in ectopic endometrium, and the markers S100A13, MMP-2 and -9, TF, follistatin, myostatin, ROBO1, LPA1 and 4-5, pSTAT3, IL-6 and IL-22 were increased in eutopic endometrium, compared with control endometrium. The anti-angiogenic markers E-cadherin, eukaryotic translation initiation factor 3 subunit and gene associated with retinoic-interferon-induced mortality 19 were decreased in ectopic endometrium and IL-10 in eutopic endometrium, compared with control endometrium. The staining level of vWF and two pro-angiogenic markers (NF-κB nuclear p65 and TF) correlated with AUB in patients with adenomyosis. We found no studies that investigated the possible relationship between markers of angiogenesis and subfertility in adenomyosis patients. Nine articles reported on direct or indirect targeting of angiogenesis in adenomyosis—either by testing hormonal therapy or herbal compounds in clinical studies or by testing angiogenesis inhibitors in preclinical studies. However, there are no clinical studies on the effectiveness of such therapy for adenomyosis-related AUB or subfertility.Wider implicationsThe results are in agreement with our hypothesis that increased angiogenesis is present in the endometrium of patients with adenomyosis compared with the endometrium of control patients. It is likely that increased angiogenesis leads to fragile and more permeable vessels resulting in adenomyosis-related AUB and possibly subfertility. While this association has not sufficiently been studied yet, our results encourage future studies to investigate the exact role of angiogenesis in the etiology of adenomyosis and related AUB or subfertility in women with adenomyosis in order to design curative or preventive therapeutic strategies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Role of angiogenesis in adenomyosis-associated abnormal uterine bleeding and subfertility: a systematic review

Harmsen

Wong

Mijatovic

et al. 2019

Human Reproduction Update

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“…In mice, administration of the anti-angiogenic agent Cabergoline (Pfizer) was able to reduce both vascularization and innervation of lesions in a mouse model of endometriosis (22), and studies in a transgenic mouse model have demonstrated that overexpression of Slit2 increases microvascular density in both eutopic endometrium and lesions (23). In women, immunostaining of ovarian endometriomas with a pan-SLIT antibody was correlated with recurrence of lesions (24,25), but to date, no studies have examined expression in peritoneal lesions.…”

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confidence: 99%

Estrogen Receptor (ER) Agonists Differentially Regulate Neuroangiogenesis in Peritoneal Endometriosis via the Repellent Factor SLIT3

et al. 2014

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Endometriosis is an estrogen-dependent neurovascular disorder characterized by growth of endometrial tissue (lesions) outside the uterine cavity. Patients suffer chronic pelvic pain, and it has been proposed that co-recruitment of nerves/blood vessels (neuroangiogenesis) into the lesions is fundamental to the development of painful symptoms. We hypothesized that estrogen-dependent regulation of axonal guidance molecules of the SLIT/ROBO (Roundabout) family could play a role in neuroangiogenesis occurring in endometriosis lesions found on the peritoneal wall. In tissue samples from human patients and a mouse model of endometriosis, concentrations of mRNA encoded by SLIT3 were significantly higher in lesions than normal peritoneum. Estrogen regulation of SLIT3 was investigated using 17β-estradiol and selective agonists for each subtype of estrogen receptor (ER) (ERα agonist, 4,4',4″-(4-propyl-(1H)-pyrazole-1,3,5-tryl) trisphenol; ERβ agonist, 2,3-bis(4-hydroxy-phenyl)-propionitrile [DPN]). In mice, DPN (EC50 0.85) increased Slit3 mRNA concentrations compared with hormone-depleted and 17β-estradiol-treated (EC50 0.1) animals and decreased the density of nerves but not vessels in endometriosis lesions. SLIT3 mRNA concentrations were increased in DPN-treated human endometrial endothelial cells and in 4,4',4″-(4-propyl-(1H)-pyrazole-1,3,5-tryl) trisphenol-treated (EC50 200) rat dorsal root ganglia neurons. Functional assays (neurite outgrowth, network formation) revealed that SLIT3 promotes angiogenesis but decreases neurogenesis. In conclusion, these data suggest that estrogen-dependent expression of SLIT3 may play a key role in regulating nerve-vessel interactions within the complex microenvironment of endometriosis lesions.

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“…The positive correlation between SLIT and DNMT1 staining levels in eutopic endometrium was unexpected, but given that SLIT immunoreactivity is found to be correlated with microvascular density in endometriosis [32], endometrial cancer [33] and also in adenomyosis [20], it is possible that increased SLIT staining in eutopic endometrium may increase vascular permeability, resulting in an increased amount of menses. This may explain our finding that higher DNMT1 staining in eutopic endometrium is associated with heavier menses.…”

Section: Discussionmentioning

confidence: 99%

“…We also correlated their immunoreactivity levels with the patients’ symptomology such as dysmenorrhea status and/or severity, amount of menses, and uterus size. Finally, we evaluated correlation coefficients of the DNMT immunoreactivity levels with other proteins that we have reported previously, including NF-ĸB [19], SLIT [20], oxytocin receptor (OTR) and transient receptor potential vanilloid type 1 (TRPV1) [21]. This may provide some much needed clues suggesting that some of these aberrations may be epigenetically controlled.…”

Section: Introductionmentioning

confidence: 99%

Aberrant Immunoreactivity of Deoxyribonucleic Acid Methyltransferases in Adenomyosis

Liu

Guo²

2012

Gynecol Obstet Invest

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Objectives: To investigate the expression and localization of deoxyribonucleic acid methyltransferases (DNMTs) in women with and without adenomyosis. Study Design: Ectopic and homologous eutopic endometrium from 50 women with adenomyosis and endometrium from 18 age- and menstrual phase-matched women without adenomyosis were used for immunohistochemical analysis. Tissue sections were immunostained with DNMT1, DNMT3A, and DNMT3B. Microscopic evaluation to assess the presence and localization of DNMT1, DNMT3A, and DNMT3B throughout the menstrual cycle in both eutopic endometrial and endometriotic tissues of women with adenomyosis was performed, and comparison with normal endometrium was made. Results: Compared with normal endometrium, immunoreactivity to DNMT1 and DNMT3B was higher in ectopic endometrium, while DNMT3A staining levels were significantly reduced in both eutopic and ectopic endometrium. DNMT1 immunoreactivity in eutopic endometrium was positively associated with heavier menses. Increased DNMT3B immunoreactivity in ectopic, but not eutopic, endometrium was associated with the severity of dysmenorrhea. Conclusions: The immunoreactivity to DNMTs in adenomyosis differs significantly from that in normal endometrium, suggesting that adenomyosis may be an epigenetic disease. The finding that DNMT3B correlates with the severity of dysmenorrhea suggests that DNMTs may be involved in adenomyosis-caused dysmenorrhea and its severity. Thus, therapeutics based on epigenetic rectification may hold promise in the management of adenomyosis.

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Increased immunoreactivity to SLIT/ROBO1 and its correlation with severity of dysmenorrhea in adenomyosis

Cited by 24 publications

References 24 publications

Role of angiogenesis in adenomyosis-associated abnormal uterine bleeding and subfertility: a systematic review

Role of angiogenesis in adenomyosis-associated abnormal uterine bleeding and subfertility: a systematic review

Estrogen Receptor (ER) Agonists Differentially Regulate Neuroangiogenesis in Peritoneal Endometriosis via the Repellent Factor SLIT3

Aberrant Immunoreactivity of Deoxyribonucleic Acid Methyltransferases in Adenomyosis

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