Blocking of Stromal Cell-Derived Factor-1 Reduces Neoangiogenesis in Human Endometriosis Lesions in a Mouse Model

Virani, Sophia; Edwards, Andrew K.; Thomas, Richard; Childs, Timothy; Tayade, Chandrakant

doi:10.1111/aji.12134

Cited by 17 publications

(16 citation statements)

References 46 publications

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“…The cytokine profile suggests a potential involvement of IL-17A in mediating neo-angiogenesis and recruitment of lymphocytes and bone-marrow derived cells to the site of lesion development. In earlier studies, we (31) and others (32) showed that CXCL12 contributes to the recruitment of endothelial progenitor cells at the endometriotic lesions and aid neo-angiogenesis.…”

Section: Resultsmentioning

confidence: 84%

“…Concentrations of cytokines such as TNF-α, IL-6 and IL-8 are increased in the peritoneal fluid and are augmented in production from activated peritoneal macrophages, which primarily contribute to the inflammatory milieu associated with pathogenesis of the disease. Furthermore, secretory factors from immune cells mediate vascularization of endometriotic lesions through both neo-angiogenesis stimulated by VEGF (30) and de novo vasculogenesis at the site of implantation through recruitment of bone-marrow derived endothelial progenitor cells (EPCs) (31, 32). Emerging evidences from cancer and autoimmune literature suggest that IL-17A contributes to the neo-angiogenesis and perpetuates inflammatory responses (25, 33), but there are few reports investigating the role of IL-17A in the pathogenesis of endometriosis.…”

Section: Introductionmentioning

confidence: 99%

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IL-17A Contributes to the Pathogenesis of Endometriosis by Triggering Proinflammatory Cytokines and Angiogenic Growth Factors

Ahn

Edwards

Singh

et al. 2015

The Journal of Immunology

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152

114

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Endometriosis is a chronic, inflammatory disease characterized by the growth of endometrial tissue in aberrant locations outside the uterus. Neo-angiogenesis or establishment of new blood supply is one of the fundamental requirements of endometriotic lesion survival in the peritoneal cavity. IL-17A is emerging as a potent angiogenic and pro-inflammatory cytokine involved in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis and psoriasis. However, sparse information is available in the context of endometriosis. In this study, we demonstrate the potential importance of IL-17A in the pathogenesis and pathophysiology of endometriosis. The data show a differential expression of IL-17A in human ectopic endometriotic lesions and matched eutopic endometrium from women with endometriosis. Importantly, surgical removal of lesions resulted in significantly reduced plasma IL-17A concentrations. Immunohistochemistry revealed localization of IL-17A primarily in the stroma of matched ectopic and eutopic tissue samples. In vitro stimulation of endometrial epithelial carcinoma cells, Ishikawa cells and human umbilical vein endothelial cells with IL-17A revealed significant increase in angiogenic (VEGF, IL-8), pro-inflammatory (IL-6, IL-1β) and chemotactic cytokines (G-CSF, CXCL12, CXCL1, CX3CL1). Furthermore, IL-17A promoted tubulogenesis of HUVECs plated on matrigel in a dose-dependent manner. Thus we provide the first evidence that endometriotic lesions produce IL-17A and that the removal of the lesion via laparoscopic surgery leads to the significant reduction in the systemic levels of IL-17A. Taken together, our data shows a likely important role of IL-17A in promoting angiogenesis and pro-inflammatory environment in the peritoneal cavity for the establishment and maintenance of endometriosis lesions.

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Section: Resultsmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

IL-17A Contributes to the Pathogenesis of Endometriosis by Triggering Proinflammatory Cytokines and Angiogenic Growth Factors

Ahn

Edwards

Singh

et al. 2015

The Journal of Immunology

Self Cite

152

114

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“…Stromal cellderived factor-1/chemokine receptor type-4 signaling, in turn, also regulates the homing of EPCs to endometriotic lesions. 15,48 In addition, our gene expression profile analysis revealed a strong up-regulation of the genes coding for early growth response 3, nuclear receptor corepressor 2, and plasma kallikrein B1 in estrogen-treated lesions. Both early growth response 3 and nuclear receptor corepressor 2 have been shown to promote angiogenesis.…”

Section: Epcs In Endometriosismentioning

confidence: 79%

Estrogen Stimulates Homing of Endothelial Progenitor Cells to Endometriotic Lesions

Rudzitis‐Auth

Nenicu

Nickels

et al. 2016

The American Journal of Pathology

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The incorporation of endothelial progenitor cells (EPCs) into microvessels contributes to the vascularization of endometriotic lesions. Herein, we analyzed whether this vasculogenic process is regulated by estrogen. Estrogen- and vehicle-treated human EPCs were analyzed for migration and tube formation. Endometriotic lesions were induced in irradiated FVB/N mice, which were reconstituted with bone marrow from FVB/N-TgN (Tie2/green fluorescent protein) 287 Sato mice. The animals were treated with 100 μg/kg β-estradiol 17-valerate or vehicle (control) over 7 and 28 days. Lesion growth, cyst formation, homing of green fluorescent protein(+)/Tie2(+) EPCs, vascularization, cell proliferation, and apoptosis were analyzed by high-resolution ultrasonography, caliper measurements, histology, and immunohistochemistry. Numbers of blood circulating EPCs were assessed by flow cytometry. In vitro, estrogen-treated EPCs exhibited a higher migratory and tube-forming capacity when compared with controls. In vivo, numbers of circulating EPCs were not affected by estrogen. However, estrogen significantly increased the number of EPCs incorporated into the lesions' microvasculature, resulting in an improved early vascularization. Estrogen further stimulated the growth of lesions, which exhibited massively dilated glands with a flattened layer of stroma. This was mainly because of an increased glandular secretory activity, whereas cell proliferation and apoptosis were not markedly affected. These findings indicate that vasculogenesis in endometriotic lesions is dependent on estrogen, which adds a novel hormonally regulated mechanism to the complex pathophysiology of endometriosis.

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“…Not surprisingly, we also observed significant increase in PECAM1, CXCL10 , and CXCL12 (genes known to play role in angiogenesis) in ectopic tissues compared with eutopic and control endometrium. Indeed, we previously reported increased expression of CXCL12 protein in human endometriotic lesions compared with matched eutopic endometrium samples and demonstrated that blocking of CXCL12 in a xenograft mouse model of endometriosis affects neovascularization and survival of endometriotic lesions (29). To this end, these immune gene profiles further support that ectopic endometriotic lesion is viewed as foreign, elicits local inflammation, establishes vasculatures, and participates in the generation of pain for some patients, as suggested by increased PTGER4 expression in ectopic tissues.…”

Section: Discussionmentioning

confidence: 99%

Immune-inflammation gene signatures in endometriosis patients

Ahn

Khalaj

Young

et al. 2016

Fertility and Sterility

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146

102

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Objective To determine if the molecular profiles of endometriotic lesions contain informative measures of inflammation and immune dysfunction that may contribute to better understanding of the interplay between immune dysfunction and inflammation and their contribution to endometriosis pathogenesis. Design Immune and inflammation transcriptomic analysis with the use of the Nanostring nCounter GX Human Immunology V2 platform (579 human immune and inflammation–related genes and 15 housekeeping genes). Setting Academic university and teaching hospital. Intervention(s) None. Patient(s) Stage III–IV endometriosis patients with infertility (n = 8) and fertile disease-free control women undergoing tubal ligation (n = 8). Menstrual stage was matched to secretory phase in all participants. Main Outcome Measure(s) Immune and inflammation transcriptomics quantification from ectopic endometriotic lesions and matched eutopic endometrium from patients. Endometria of fertile women served as control subjects. Result(s) Our results displayed endometriotic lesions as molecularly distinct entities compared with eutopic endometrium and endometrium of control samples; 396 out of 579 screened immune and inflammation–related genes were significantly different in ectopic tissues compared with control endometrium. Most importantly, eutopic endometrium of the patients displayed a unique molecular profile compared with the control endometrium (91/579 genes were significantly different), particularly of genes involved in regulation of cell apoptosis and decidualization. Conclusion(s) We characterize differential expression of immune-inflammation genes in endometriosis patients, and show molecular distinction of eutopic endometrium of patients compared with control fertile women.

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Blocking of Stromal Cell-Derived Factor-1 Reduces Neoangiogenesis in Human Endometriosis Lesions in a Mouse Model

Abstract: Blocking SDF-1 reduces neovascularization and survival of lesions in a mouse model of endometriosis.

Cited by 17 publications

References 46 publications

IL-17A Contributes to the Pathogenesis of Endometriosis by Triggering Proinflammatory Cytokines and Angiogenic Growth Factors

IL-17A Contributes to the Pathogenesis of Endometriosis by Triggering Proinflammatory Cytokines and Angiogenic Growth Factors

Estrogen Stimulates Homing of Endothelial Progenitor Cells to Endometriotic Lesions

Immune-inflammation gene signatures in endometriosis patients

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