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Obstetrics and Gynecology International
Volume 2013 (2013), Article ID 859619, 8 pages
Angiogenesis and Endometriosis
1Department of Obstetrics and Gynecology, Division of Human Reproduction, Federal University of Minas Gerais, 310130-100 Belo Horizonte, MG, Brazil
2Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC 27157-1066, USA
Received 15 February 2013; Accepted 24 April 2013
Academic Editor: Pasquapina Ciarmela
Copyright © 2013 Ana Luiza L. Rocha et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A comprehensive review was performed to survey the role of angiogenesis in the pathogenesis of endometriosis. This is a multifactorial disease in which the development and maintenance of endometriotic implants depend on their invasive capacity and angiogenic potential. The peritoneal fluid of patients with endometriosis is a complex suspension carrying inflammatory cytokines, growth factors, steroid hormones, proangiogenic factors, macrophages, and endometrial and red blood cells. These cells and their signaling products concur to promote the spreading of new blood vessels at the endometriotic lesions and surroundings, which contributes to the endometriotic implant survival. Experimental studies of several antiangiogenic agents demonstrated the regression of endometriotic lesions by reducing their blood supply. Further studies are necessary before these novel agents can be introduced into clinical practice, in particular the establishment of the safety of anti-angiogenic medications in women who are seeking to become pregnant.
Endometriosis is a benign sex hormone-dependent gynecological disease, characterized by the presence and growth of endometrial tissue outside the uterus; it affects 10% of women of reproductive age and is associated with infertility and pain [1, 2]. The symptoms can impact on general physical, mental, and social well-being . Despite many investigations about endometriosis, the pathogenesis of the disease remains unclear . The disease derives from retrograde menstruation of endometrial cells which implant on peritoneal surfaces and induce an inflammatory response. The success of the ectopic implants depends on other pathological processes such as neoangiogenesis, fibrosis, adhesion formation, avoidance of apoptosis, immune dysfunction, and neuronal infiltration [1, 2, 4–7].
During normal reproduction, cyclic angiogenesis is orchestrated by the endocrine system, providing physiological signals for follicular maturation, corpus luteum function, endometrial growth, and remodeling . Endometriosis is a multifactorial disease in which angiogenesis also plays an important role [9–13]. The angiogenic potential of both the endometrium and the peritoneal environment influences lesion establishment [9–12]. Indeed, endometriotic lesions require an adequate blood supply to survive in their ectopic sites.
The goals of endometriosis treatment alternate between alleviation of pelvic pain and successful achievement of pregnancy in infertile patients. Antiangiogenic drugs hold a promise for both indications and present a distinct perspective in endometriosis treatment.
The aim of this paper is to review the literature evidence of the important role of angiogenesis in the pathogenesis of endometriosis and to establish the rationale for anti-angiogenic agents as a new therapeutic option in the treatment of endometriosis patients.
2.1. Search Strategy
A literature search was performed to survey the role of angiogenesis in the pathogenesis of endometriosis. Articles were identified through the following electronic databases: MEDLINE (until January 2013) and the Cochrane Central Register of Controlled Trials (The Cochrane Library until January 2013). A combination of Medical Subject Headings (MeSH) and text words was used to generate the list of citations: (endometriosis OR “endometriotic lesions”) AND (angiogenesis OR “angiogenic factors” OR vasculogenesis OR “antiangiogenic drugs”). All pertinent articles were examined and their reference lists were reviewed in order to identify other studies for potential inclusion in this review. No institutional review board approval was required because only published data were analyzed.
2.2. Selection Criteria
Randomized controlled trials (RCTs), patient preference trials, observational studies, case reports, and proceedings of scientific meetings were included in this review, whereas abstracts were excluded. Only publications in English were considered in our selection. The abstracts of studies identified in the search were reviewed to exclude irrelevant or repeat citations. The reviewers were not blinded to the names of investigators or sources of publication.
3.1. Angiogenesis in Endometrium and in Endometriotic Implants
Endometriotic lesions are typically characterized by a dense vascularization that occurs through angiogenesis process [1, 9, 14]. In normal eutopic (intrauterine) endometrium, it has been suggested that vessel elongation, rather than branch point sprouting, is the primary mechanism for rapid vessel growth during the proliferative phase , but the precise mechanism in endometriosis lesions has not been evaluated to date. Recruitment of new capillaries from existing, adjacent peritoneal microvessels was postulated ; however, the derivation of new blood vessels from circulating endothelial progenitor cells (EPCs), the so-called “vasculogenesis,” also appears to be important in the pathogenesis of endometriosis . The endometrium is a dynamic tissue exhibiting populations of clonogenic epithelial and stromal stem cells [16–18] that require active cyclic angiogenesis. Bone-marrow-derived EPCs can be detected in developing endometriotic lesions  and those lesions show increased expression of factors and chemokines that participate in EPC recruitment, such as hypoxia-inducible-factor- (HIF-) 1α and stromal-cell-derived-factor- (SDF-) 1 [14, 20]. Moreover, the presence of hypoxia, endothelial injury, and inflammation and the expression of ER-α contribute to the mobilization and recruitment of EPCs from the bone marrow into endometriotic lesions [14, 21–27].
Endometriotic lesions can produce cytokines and growth factors that regulate their proliferation and vascularization. Interleukin- (IL-) 1, the dominant IL-1 secreted by activated peritoneal macrophages, plays an important role in the neovascularization of endometriotic lesions [28, 29]. Cultured human endometrial stromal cells (HESC) from women with endometriosis secrete IL-6 and IL-8 robustly . IL-6 is a potent multifunctional protein, which promotes endometrial cell proliferation  and angiogenesis ; its secretion is elevated in ectopic endometrial tissue and its concentrations are high in peritoneal fluid of patients with endometriosis . IL-8 is a proinflammatory cytokine that induces chemotaxis of neutrophils and has a potent stimulatory effect on angiogenesis [34, 35].
Activin A is a growth factor member of the transforming growth factor β superfamily with effects on inflammation and angiogenesis [36–38]. The human endometrium is both a source and a target of activin A, which is able to modulate the expression and secretion of IL-8 and vascular endothelial growth factor (VEGF), from human endometrial stromal cells . VEGF is among the most potent and specific angiogenic factors. Its effects include endothelial cell proliferation, migration, organization into tubules, and enhanced permeability, all of which participate in the angiogenic cascade . Endometrial VEGF expression is enhanced by estradiol and its concentrations are correlated with neovascularization and increased vascular permeability during late proliferative phase . Cyclic changes in VEGF expression throughout menstrual cycle are observed with maximal expression during the secretory phase and menstruation [9, 41, 42]. VEGF was observed in the epithelium and in stromal cells of endometriotic implants, being more expressed in the epithelium [18, 42]. Moreover, endometriotic cells can synthesize and secrete VEGF .
Activated peritoneal macrophages and neutrophils also have the capacity to produce and secrete VEGF [18, 43, 44]. Some studies demonstrated that the expression and concentration of VEGF are increased in tissue from endometriotic patients [45–49]. Endometriomas and red implants show the highest concentrations of VEGF [45, 46]. The expression and secretion of VEGF from human endometrial stromal cells are modulated by activin A .
3.2. Peritoneal Fluid from Patients with Endometriosis
The peritoneal fluid of patients with endometriosis is a complex suspension carrying inflammatory cytokines, growth factors, steroid hormones, proangiogenic factors, macrophages, and endometrial and red blood cells [42, 43, 50–52]. Leukocytes circulating in the peritoneal fluid of patients can produce and release high amounts of VEGF [18, 43, 44]. Moreover, the peritoneal fluid concentrations of VEGF in patients with endometriosis correlate with the stage of the disease . Other proangiogenic factors, namely, IL-8 [30, 53–56], hepatocyte growth factor (HGF) [57, 58], erythropoietin , angiogenin , macrophage migration inhibitory factor , neutrophil-activating factor , and TNF- [63, 64], are all found at increased concentrations in the peritoneal fluid of patients with endometriosis. This proangiogenic milieu is reinforced by reduced concentrations of antiangiogenic factors, such as adiponectin  and interferon-gamma-induced protein 10 (IP-10) [66, 67], although levels of the endogenous VEGF antagonist soluble Flt-1 were reported to be increased in the pelvic fluid of endometriosis cases .
3.3. Agents with Antiangiogenic Properties
As one of the most potent angiogenic factors, VEGF is postulated to be involved in the progress of the ectopic lesions in endometriosis [22, 67]. Vascularization and VEGF and its receptor expression are particularly high in deeply infiltrating endometriosis, supporting the hypothesis that antiangiogenic therapy (Table 1) could represent a new and promising modality of treatment of this symptomatic disease manifestation . Classic treatments of endometriosis rely on the use of hormonal drugs with undesirable menopausal side effects or surgery, with its risks of complications, frequent recurrence, and common need for adjuvant medical therapy. New agents, like antiangiogenic factors, offer a different perspective in endometriosis therapy, but their development will necessitate the monitoring of potential side effects.
3.4. VEGF Blockers and Inhibitors
Soluble truncated VEGF receptors (Flt-1) and affinity-purified goat antibodies to human VEGF-A inhibited the growth of human endometrium fragments implanted into nude mice . In similar studies, treatment with anti-human VEGF antibody resulted in a significant decrease in the number of lesions of endometriosis in the nude mouse model . The angiogenesis inhibitors TNP-470, endostatin, and anginex inhibited the number of endometriosis lesions present in a mice model . Lodamin, an oral nontoxic formulation of TNP-470, suppressed the mobilization of circulating endothelial cells and endothelial progenitor cells and inhibited the growth of endometriotic lesion in a mouse model of endometriosis, demonstrating a potential clinical use of antiangiogenic therapy for endometriosis .
Bevacizumab, a full-length recombinant humanized monoclonal antibody that inhibits VEGF, inhibited the development and cell proliferation in endometriotic lesions, reduced vascular density, increased apoptosis, and reduced VEGF levels in peritoneal fluid in a murine model of endometriosis . Bevacizumab reduced the volume of endometriotic implants but did not show any detrimental effect on ovarian reserve in a rat model of induced endometriosis .
Sorafenib, another anti-angiogenic agent, is an orally active multikinase inhibitor that interferes with the activity of the VEGF receptor, along with other tyrosine kinase receptors. This drug reduced the microvessel density and lesion volume of endometrial implants in a rat model of induced endometriosis .
Hypoacetylation of histone H4 is associated with downregulation of the p53 and von Hippel-Lindau proteins and the upregulation of HIF-1α. All three effects promote VEGF gene expression . Romidepsin, a histone deacetylase inhibitor, may be a potential therapeutic candidate against angiogenesis in endometriosis. This agent inhibited VEGF gene transcription, protein expression, and secretion of VEGF in an in vitro study with human immortalized epithelial endometriotic cells .
Lipoxin A4 (LXA4) is an endogenous eicosanoid which participates in the regulation of inflammation. This lipid can block migration of endothelial cells and VEGF-stimulated angiogenesis . In endometriosis induced in BALB/c mice, LXA4 reduced the endometriosis lesion size and downregulated inflammation-associated proteins, including IL-6 VEGF and matrix metalloproteinase 9 . 4-Hydroxybenzyl alcohol (HBA) is a naturally occurring phenolic compound, found in many plants, including carrots . HBA exhibits an anti-inflammatory activity and the development of new blood vessels . HBA inhibited the initiation of the angiogenic process by downregulating VEGF and matrix-metalloproteinase-(MMP-) 9 expression and by affecting endothelial cell migration in vitro and in vivo [78, 79].
Parecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, reduced lesion size, microvessel density, the number of macrophages, and the expression of VEGF and led to atrophy and regression of endometrial implants in a rat model of peritoneal endometriosis .
The major constituent of green tea, Epigallocatechin gallate, also appears to have antiangiogenic properties since its use decreased endometriotic lesion size, microvessel diameter and density, and VEGF mRNA expression in an experimental SCID mouse model of endometriosis . Moreover, this extract from green tea increased apoptosis in the endometriotic lesions . Another study confirmed that Epigallocatechin gallate blocked VEGF expression of hamster endometrial cells in vitro and inhibited angiogenesis and blood perfusion of endometriotic lesions in vivo, inducing regression of the endometriotic lesions . These antiangiogenic and proapoptotic proprieties of green tea suggest that it might be used as a complementary treatment in endometriosis, but its potential benefit remains to be evaluated in clinical trials. Combined inhibition of VEGF, fibroblast growth factor, and platelet-derived growth factor by inhibitor SU6668 suppresses angiogenesis and vessel maturation in endometriotic lesions in an animal model .
Macrophage migration inhibitory factor (MIF), which is markedly upregulated in active endometriosis lesions , also contributes to angiogenesis. An MIF antagonist suppressed the development of endometriotic lesions in vivo reducing the expression of VEGF, cell adhesion receptors, MMP-2, MMP-9, IL-8, and cyclooxygenase- (COX-) 2. Moreover, MIF antagonist demonstrated a proapoptotic action in the nude mouse model .
3.5. Other Antiangiogenic Agents
Retinoic acid, known to have anti-angiogenic proprieties, decreased the volume of endometriotic implants in mouse  and rat  models of induced endometriosis. Xanthohumol, a prenylated flavonoid isolated from hops, demonstrated the capacity to inhibit the formation of new blood vessels in developing peritoneal and mesenteric endometriotic lesions which were surgically induced in BALB/c mice, without affecting the histomorphology of the uterus or ovary . Rapamycin, an immunosuppressant drug with antiangiogenic effects, induced regression of endometriotic lesions by inhibiting neovascularization and cell proliferation in an in vitro model .
Progestogens (progesterone, dydrogesterone, or its metabolite dihydrodydrogesterone) reduced proliferation of endometrial stromal cells and suppressed the transcription of VEGF-A and the microvessel density in human ectopic endometrial lesions in a mouse model, regulating important factors for the establishment of ectopic lesions . Dienogest reduced IL-1β production from peritoneal macrophages and implant volume in a rat model of endometriosis .
Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase with intrinsic antioxidant, anti-inflammatory, and anti-angiogenic properties . Atorvastatin inhibited the inflammatory and angiogenic genes COX-2 and VEGF in endometriotic stromal cells . Cell proliferation and angiogenesis were inhibited by lovastatin in a dose-dependent manner in a three-dimensional in vitro model of endometrium .
The dopamine agonist cabergoline exerts antiangiogenic effects through VEGFR-2 inactivation inhibiting the growth of established endometriosis lesions . Moreover, cabergoline treatment results in a significantly lower expression of VEGF and VEGFR-2 in endometriotic lesions . Quinagolide, binding to dopamine D2 receptor, downregulated VEGF/VEGFR2, inhibited neoangiogenesis, and reduced the size of active endometriotic lesions .
A comprehensive synthesis of the complex pathogenesis of endometriosis remains elusive, but we know that this is a multifactorial disease in which the development and maintenance of endometriotic implants depend on their invasive capacity and angiogenic potential (Figure 1).
As angiogenesis represents a critical step in the establishment and pathogenesis of endometriosis, this process has been viewed as a potential new target for therapeutic intervention. In this review, experimental studies of several anti-angiogenic agents demonstrated the regression of endometriotic lesions by reducing their blood supply (Table 1). Further studies are necessary before these novel agents can be introduced into clinical practice, in particular the establishment of the safety of anti-angiogenic medications in women who are seeking to become pregnant. Precautions such as those instituted for the prescription of retinoic acid should be considered to avoid the possible consequences of impaired blood vessel formation to the developing embryo and placenta. With this provision, anti-angiogenic treatments offer novel perspectives and mechanisms and promise more effective adjuvant therapies for patients with endometriosis.
Research in the laboratories of the authors has been supported by FAPEMIG, CNPq, Brazilian National Institute of Hormones and Women’s Health, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health (USA) as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research (U54 HD55787).
- L. C. Giudice, “Clinical practice. Endometriosis,” New England Journal of Medicine, vol. 362, no. 25, pp. 2389–2398, 2010.
- S. E. Bulun, “Endometriosis,” New England Journal of Medicine, vol. 360, no. 3, pp. 268–279, 2009.
- S. Kennedy, A. Bergqvist, C. Chapron et al., “ESHRE guideline for the diagnosis and treatment of endometriosis,” Human Reproduction, vol. 20, no. 10, pp. 2698–2704, 2005.
- K. J. Berkley, A. J. Rapkin, and R. E. Papka, “The pains of endometriosis,” Science, vol. 308, pp. 1587–1589, 2005.
- L. C. Giudice, R. O. Swiersz, and L.M. Burney, “Endometriosis,” in Endocrinology, J. L. Jameson and L. J. De Groot, Eds., pp. 2356–2370, Elsevier, New York, NY, USA, 6th edition, 2010.
- N. Tokushige, R. Markham, P. Russell, and I. S. Fraser, “Nerve fibres in peritoneal endometriosis,” Human Reproduction, vol. 21, no. 11, pp. 3001–3007, 2006.
- L. C. Giudice and L. C. Kao, “Endometriosis,” Lancet, vol. 364, no. 9447, pp. 1789–1799, 2004.
- R. B. Jaffe, “Importance of angiogenesis in reproductive physiology,” Seminars in Perinatology, vol. 24, no. 1, pp. 79–81, 2000.
- J. McLaren, “Vascular endothelial growth factor and endometriotic angiogenesis,” Human Reproduction Update, vol. 6, no. 1, pp. 45–55, 2000.
- R. N. Taylor, D. I. Lebovic, and M. D. Mueller, “Angiogenic factors in endometriosis,” Annals of the New York Academy of Sciences, vol. 955, pp. 89–100, 2002.
- R. N. Taylor, J. Yu, P. B. Torres et al., “Mechanistic and therapeutic implications of angiogenesis in endometriosis,” Reproductive Sciences, vol. 16, no. 2, pp. 140–146, 2009.
- A. L. Rocha, F. M. Reis, and F. Petraglia, “New trends for the medical treatment of endometriosis,” Expert Opinion on Investigational Drugs, vol. 21, no. 7, pp. 905–919, 2012.
- D. E. Machado, M. S. Abrao, P. T. Berardo, C. M. Takiya, and L. E. Nasciutti, “Vascular density and distribution of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) are significantly higher in patients with deeply infiltrating endometriosis affecting the rectum,” Fertility and Sterility, vol. 90, no. 1, pp. 148–155, 2008.
- M. W. Laschke, C. Giebels, and M. D. Menger, “Vasculogenesis: a new piece of the endometriosis puzzle,” Human Reproduction Update, vol. 17, no. 5, pp. 628–636, 2011.
- L. S. Gambino, N. G. Wrefordm, J. F. Bertram, P. Dockery, F. Lederman, and P. A. W. Rogers, “Angiogenesis occurs by vessel elongation in proliferative phase human endometrium,” Human Reproduction, vol. 17, no. 5, pp. 1199–1206, 2002.
- R. W. S. Chan, K. E. Schwab, and C. E. Gargett, “Clonogenicity of human endometrial epithelial and stromal cells,” Biology of Reproduction, vol. 70, no. 6, pp. 1738–1750, 2004.
- C. E. Gargett, “Uterine stem cells: what is the evidence?” Human Reproduction Update, vol. 13, no. 1, pp. 87–101, 2007.
- C. E. Gargett and H. Masuda, “Adult stem cells in the endometrium,” Molecular Human Reproduction, vol. 16, no. 11, pp. 818–834, 2010.
- C. M. Becker, P. Beaudry, T. Funakoshi et al., “Circulating endothelial progenitor cells are up-regulated in a mouse model of endometriosis,” American Journal of Pathology, vol. 178, no. 4, pp. 1782–1791, 2011.
- C. M. Becker, N. Rohwer, T. Funakoshi et al., “2-Methoxyestradiol inhibits hypoxia-inducible factor-1α and suppresses growth of lesions in a mouse model of endometriosis,” American Journal of Pathology, vol. 172, no. 2, pp. 534–544, 2008.
- M. W. Laschke, A. Elitzsch, B. Vollmar, and M. D. Menger, “In vivo analysis of angiogenesis in endometriosis-like lesions by intravital fluorescence microscopy,” Fertility and Sterility, vol. 84, no. 2, pp. 1199–1209, 2005.
- M. W. Laschke, A. Elitzsch, B. Vollmar, P. Vajkoczy, and M. D. Menger, “Combined inhibition of vascular endothelial growth factor (VEGF), fibroblast growth factor and platelet-derived growth factor, but not inhibition of VEGF alone, effectively suppresses angiogenesis and vessel maturation in endometriotic lesions,” Human Reproduction, vol. 21, no. 1, pp. 262–268, 2006.
- M. Hristov, A. Zernecke, E. A. Liehn, and C. Weber, “Regulation of endothelial progenitor cell homing after arterial injury,” Thrombosis and Haemostasis, vol. 98, no. 2, pp. 274–277, 2007.
- A. Zampetaki, J. P. Kirton, and Q. Xu, “Vascular repair by endothelial progenitor cells,” Cardiovascular Research, vol. 78, no. 3, pp. 413–421, 2008.
- R. González-Ramos, J. Donnez, S. Defrère et al., “Nuclear factor-kappa B is constitutively activated in peritoneal endometriosis,” Molecular Human Reproduction, vol. 13, no. 7, pp. 503–509, 2007.
- E. I. Lev, Z. Estrov, K. Aboulfatova et al., “Potential role of activated platelets in homing of human endothelial progenitor cells to subendothelial matrix,” Thrombosis and Haemostasis, vol. 96, no. 4, pp. 498–504, 2006.
- H. Masuda, C. Kalka, T. Takahashi et al., “Estrogen-mediated endothelial progenitor cell biology and kinetics for physiological postnatal vasculogenesis,” Circulation Research, vol. 101, no. 6, pp. 598–606, 2007.
- D. I. Lebovic, J. L. Shifren, I. P. Ryan et al., “Ovarian steroid and cytokine modulation of human endometrial angiogenesis,” Human Reproduction, vol. 15, no. 3, pp. 67–77, 2000.
- D. I. Lebovic, F. Bentzien, V. A. Chao, E. N. Garrett, Y. G. Meng, and R. N. Taylor, “Induction of an angiogenic phenotype in endometriotic stromal cell cultures by interleukin-1β,” Molecular Human Reproduction, vol. 6, no. 3, pp. 269–275, 2000.
- A. L. Rocha, P. Carrarelli, R. Novembri et al., “Activin A stimulates interleukin 8 and vascular endothelial growth factor release from cultured human endometrial stromal cells: possible implications for the pathogenesis of endometriosis,” Reproductive Sciences, vol. 19, no. 8, pp. 832–838, 2012.
- L. C. Giudice, “Growth factors and growth modulators in human uterine endometrium: their potential relevance to reproductive medicine,” Fertility and Sterility, vol. 61, no. 1, pp. 1–17, 1994.
- T. Cohen, D. Nahari, L. W. Cerem, G. Neufeld, and B. Z. Levin, “Interleukin 6 induces the expression of vascular endothelial growth factor,” Journal of Biological Chemistry, vol. 271, no. 2, pp. 736–741, 1996.
- J. A. Keenan, T. T. Chen, N. L. Chadwell, D. S. Torry, and M. R. Caudle, “Interferon-gamma (IFN-γ) and interleukin-6 (IL-6) in peritoneal fluid and macrophage-conditioned media of women with endometriosis,” American Journal of Reproductive Immunology, vol. 32, no. 3, pp. 180–183, 1994.
- A. E. Koch, M. V. Volin, J. M. Woods, et al., “Regulation of angiogenesis by the C-X-C chemokines interleukin-8 and epithelial neutrophil activating peptide 78 in the rheumatoid joint,” Arthritis and Rheumatism, vol. 44, no. 1, pp. 31–40, 2001.
- A. Arici, “Local cytokines in endometrial tissue: the role of interleukin-8 in the pathogenesis of endometriosis,” Annals of the New York Academy of Sciences, vol. 955, pp. 101–109, 2002.
- K. L. Jones, D. M. D. Kretser, S. Patella, and D. J. Phillips, “Activin A and follistatin in systemic inflammation,” Molecular and Cellular Endocrinology, vol. 225, no. 1-2, pp. 119–125, 2004.
- D. J. Phillips, D. M. de Kretser, and M. P. Hedger, “Activin and related proteins in inflammation: not just interested bystanders,” Cytokine and Growth Factor Reviews, vol. 20, no. 2, pp. 153–164, 2009.
- P. Bertolino, M. Deckers, F. Lebrin, and P. Ten Dijke, “Transforming growth factor-β signal transduction in angiogenesis and vascular disorders,” Chest, vol. 128, no. 6, pp. 585S–590S, 2005.
- P. Florio, M. Gabbanini, L. E. Borges et al., “Activins and related proteins in the establishment of pregnancy,” Reproductive Sciences, vol. 17, no. 4, pp. 320–330, 2010.
- M. D. Mueller, J. L. Vigne, A. Minchenko, D. I. Lebovic, D. C. Leitman, and R. N. Taylor, “Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors α and β,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 20, pp. 10972–10977, 2000.
- D. S. Charnock-Jones, A. M. MacPherson, D. F. Archer et al., “The effect of progestins on vascular endothelial growth factor, oestrogen receptor and progesterone receptor immunoreactivity and endothelial cell density in human endometrium,” Human Reproduction, vol. 15, no. 3, pp. 85–95, 2000.
- J. L. Shifren, J. F. Tseng, C. J. Zaloudek et al., “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,” Journal of Clinical Endocrinology and Metabolism, vol. 81, no. 8, pp. 3112–3118, 1996.
- J. McLaren, A. Prentice, D. S. Charnock-Jones et al., “Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids,” Journal of Clinical Investigation, vol. 98, no. 2, pp. 482–489, 1996.
- M. D. Mueller, D. I. Lebovic, E. Garrett, and R. N. Taylor, “Neutrophils infiltrating the endometrium express vascular endothelial growth factor: potential role in endometrial angiogenesis,” Fertility and Sterility, vol. 74, no. 1, pp. 107–112, 2000.
- J. Donnez, P. Smoes, S. Gillerot, F. Casanas-Roux, and M. Nisolle, “Vascular endothelial growth factor (VEGF) in endometriosis,” Human Reproduction, vol. 13, no. 6, pp. 1686–1690, 1998.
- A. Fasciani, G. D'Ambrogio, G. Bocci, M. Monti, A. R. Genazzani, and P. G. Artini, “High concentrations of the vascular endothelial growth factor and interleukin-8 in ovarian endometriomata,” Molecular Human Reproduction, vol. 6, no. 1, pp. 50–54, 2000.
- M. Takehara, M. Ueda, Y. Yamashita, Y. Terai, Y. C. Hung, and M. Ueki, “Vascular endothelial growth factor a and C gene expression in endometriosis,” Human Pathology, vol. 35, no. 11, pp. 1369–1375, 2004.
- J. Gilabert-Estellés, L. A. Ramón, F. España, et al., “Expression of angiogenic factors in endometriosis: relationship to fibrinolytic and metalloproteinase systems,” Human Reproduction, vol. 22, no. 8, pp. 2120–2127, 2007.
- M. Ulukus, H. Cakmak, and A. Arici, “The role of endometrium in endometriosis,” Journal of the Society for Gynecologic Investigation, vol. 13, no. 7, pp. 467–476, 2006.
- P. R. Koninckx, S. H. Kennedy, and D. H. Barlow, “Endometriotic disease: the role of peritoneal fluid,” Human Reproduction Update, vol. 4, no. 5, pp. 741–751, 1998.
- R. Cosín, J. Gilabert-Estellés, L. A. Ramón, et al., “Influence of peritoneal fluid on the expression of angiogenic and proteolytic factors in cultures of endometrial cells from women with endometriosis,” Human Reproduction, vol. 25, no. 2, pp. 398–405, 2010.
- R. Cosín, J. Gilabert-Estellés, L. A. Ramón et al., “Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression,” Fertility and Sterility, vol. 92, no. 4, pp. 1214–1220, 2009.
- T. Iwabe, T. Harada, T. Tsudo, M. Tanikawa, Y. Onohara, and N. Terakawa, “Pathogenetic significance of increased levels of interleukin-8 in the peritoneal fluid of patients with endometriosis,” Fertility and Sterility, vol. 69, no. 5, pp. 924–930, 1998.
- I. P. Ryan, J. F. Tseng, E. D. Schriock, O. Khorram, D. V. Landers, and R. N. Taylor, “Interleukin-8 concentrations are elevated in peritoneal fluid of women with endometriosis,” Fertility and Sterility, vol. 63, no. 4, pp. 929–932, 1995.
- A. Arici, S. I. Tazuke, E. Attar, H. J. Kliman, and D. L. Olive, “Interleukin-8 concentration in peritoneal fluid of patients with endometriosis and modulation of interleukin-8 expression in human mesothelial cells,” Molecular Human Reproduction, vol. 2, no. 1, pp. 40–45, 1996.
- E. Barcz, E. S. Rozewska, P. Kaminski, et al., “Angiogenic activity and IL-8 concentrations in peritoneal fluid and sera in endometriosis,” International Journal of Gynecology and Obstetrics, vol. 79, pp. 229–235, 2002.
- Y. Osuga, O. Tsutsumi, R. Okagaki et al., “Hepatocyte growth factor concentrations are elevated in peritoneal fluid of women with endometriosis,” Human Reproduction, vol. 14, no. 6, pp. 1611–1613, 1999.
- K. Newaz Khan, H. Masuzaki, A. Fujishita et al., “Peritoneal fluid and serum levels of hepatocyte growth factor may predict the activity of endometriosis,” Acta Obstetricia et Gynecologica Scandinavica, vol. 85, no. 4, pp. 458–466, 2006.
- S. Matsuzaki, T. Murakami, S. Uehara et al., “Erythropoietin concentrations are elevated in the peritoneal fluid of women with endometriosis,” Human Reproduction, vol. 16, no. 5, pp. 945–948, 2001.
- N. Suzumori, X. X. Zhao, and K. Suzumori, “Elevated angiogenin levels in the peritoneal fluid of women with endometriosis correlate with the extent of the disorder,” Fertility and Sterility, vol. 82, no. 1, pp. 93–96, 2004.
- R. Kats, T. Collette, C. N. Metz, and A. Akoum, “Marked elevation of macrophage migration inhibitory factor in the peritoneal fluid of women with endometriosis,” Fertility and Sterility, vol. 78, no. 1, pp. 69–76, 2002.
- J. Szamatowicz, P. Laudański, I. Tomaszewska, and M. Szamatowicz, “Chemokine growth-regulated-α: a possible role in the pathogenesis of endometriosis,” Gynecological Endocrinology, vol. 16, no. 2, pp. 137–141, 2002.
- J. W. M. Maas, C. Calhaz-Jorge, G. Ter Riet, G. A. J. Dunselman, A. F. P. M. De Goeij, and H. A. J. Struijker-Boudier, “Tumor necrosis factor-α but not interleukin-1β or interleukin-8 concentrations correlate with angiogenic activity of peritoneal fluid from patients with minimal to mild endometriosis,” Fertility and Sterility, vol. 75, no. 1, pp. 180–185, 2001.
- J. W. M. Maas, P. G. Groothuis, G. A. J. Dunselman, A. F. P. M. De Goeij, H. A. J. Struijker-Boudier, and J. L. H. Evers, “Development of endometriosis-like lesions after transplantation of human endometrial fragments onto the chick embryo chorioallantoic membrane,” Human Reproduction, vol. 16, no. 4, pp. 627–631, 2001.
- Y. Takemura, Y. Osuga, M. Harada et al., “Concentration of adiponectin in peritoneal fluid is decreased in women with endometriosis,” American Journal of Reproductive Immunology, vol. 54, no. 4, pp. 217–221, 2005.
- O. Yoshino, Y. Osuga, K. Koga et al., “Concentrations of interferon-γ-induced protein-10 (IP-10), an antiangiogenic substance, are decreased in peritoneal fluid of women with advanced endometriosis,” American Journal of Reproductive Immunology, vol. 50, no. 1, pp. 60–65, 2003.
- M. W. Laschke and M. D. Menger, “In vitro and in vivo approaches to study angiogenesis in the pathophysiology and therapy of endometriosis,” Human Reproduction Update, vol. 13, no. 4, pp. 331–342, 2007.
- S. Cho, Y. S. Choi, Y. E. Jeon et al., “Expression of vascular endothelial growth factor (VEGF) and its soluble receptor-1 in endometriosis,” Microvascular Research, vol. 83, no. 2, pp. 237–242, 2012.
- M. L. Hull, D. S. Charnock-Jones, C. L. K. Chan et al., “Antiangiogenic agents are effective inhibitors of endometriosis,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 6, pp. 2889–2899, 2003.
- A. W. Nap, A. W. Griffioen, G. A. J. Dunselman et al., “Antiangiogenesis therapy for endometriosis,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 3, pp. 1089–1095, 2004.
- A. G. Ricci, C. N. Olivares, M. A. Bilotas, G. F. Meresman, and R. I. Barañao, “Effect of vascular endothelial growth factor inhibition on endometrial implant development in a murine model of endometriosis,” Reproductive Sciences, vol. 18, no. 7, pp. 614–622, 2011.
- H. Ozer, A. Boztosun, G. Açmaz, R. Atilgan, O. B. Akkar, and M. I. Kosar, “The efficacy of bevacizumab, sorafenib, and retinoic acid on rat endometriosis model,” Reproductive Sciences, vol. 20, no. 1, pp. 26–32, 2013.
- H. Kuniyasu, Y. Chihara, and H. Kondo, “A role of histone H4 hypoacetylation in vascular endothelial growth factor expression in colon mucosa adjacent to implanted cancer in athymic mice cecum,” Pathobiology, vol. 70, no. 6, pp. 348–352, 2002.
- P. Imesch, E. P. Samartzis, M. Schneider, D. Fink, and A. Fedier, “Inhibition of transcription, expression, and secretion of the vascular epithelial growth factor in human epithelial endometriotic cells by romidepsin,” Fertility and Sterility, vol. 95, no. 5, pp. 1579–1583, 2011.
- P. Maderna and C. Godson, “Lipoxins: resolutionary road,” British Journal of Pharmacology, vol. 158, no. 4, pp. 947–959, 2009.
- Z. Xu, F. Zhao, F. Lin, J. Chen, and Y. Huang, “Lipoxin A4 inhibits the development of endometriosis in mice: the role of anti-inflammation and anti-angiogenesis,” American Journal of Reproductive Immunology, vol. 67, no. 6, pp. 491–497, 2012.
- T. Kobayashi, K. Higashi, and H. Kamada, “4-Hydroxybenzyl alcohol accumulates in flowers and developing fruits of carrot and inhibits seed formation,” Journal of Plant Physiology, vol. 160, no. 6, pp. 713–716, 2003.
- E. J. Lim, H. J. Kang, H. J. Jung, and E. H. Park, “Anti-angiogenic, anti-inflammatory and anti-nociceptive activity of 4-hydroxybenzyl alcohol,” Journal of Pharmacy and Pharmacology, vol. 59, no. 9, pp. 1235–1240, 2007.
- M. W. Laschke, A. E. V. Van Oijen, C. Scheuer, and M. D. Menger, “In vitro and in vivo evaluation of the anti-angiogenic actions of 4-hydroxybenzyl alcohol,” British Journal of Pharmacology, vol. 163, no. 4, pp. 835–844, 2011.
- D. E. Machado, P. T. Berardo, R. G. Landgraf et al., “A selective cyclooxygenase-2 inhibitor suppresses the growth of endometriosis with an antiangiogenic effect in a rat model,” Fertility and Sterility, vol. 93, no. 8, pp. 2674–2679, 2010.
- H. Xu, W. T. Lui, C. Y. Chu, P. S. Ng, C. C. Wang, and M. S. Rogers, “Anti-angiogenic effects of green tea catechin on an experimental endometriosis mouse model,” Human Reproduction, vol. 24, no. 3, pp. 608–618, 2009.
- M. W. Laschke, C. Schwender, C. Scheuer, B. Vollmar, and M. D. Menger, “Epigallocatechin-3-gallate inhibits estrogen-induced activation of endometrial cells in vitro and causes regression of endometriotic lesions in vivo,” Human Reproduction, vol. 23, no. 10, pp. 2308–2318, 2008.
- R. Kats, C. N. Metz, and A. Akoum, “Macrophage migration inhibitory factor is markedly expressed in active and early-stage endometriotic lesions,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 2, pp. 883–889, 2002.
- K. Khoufache, S. Bazin, K. Girard et al., “Macrophage migration inhibitory factor antagonist blocks the development of endometriosis in vivo,” PLoS ONE, vol. 7, no. 5, Article ID e37264, 2012.
- F. Wieser, J. Wu, Z. Shen, R. N. Taylor, and N. Sidell, “Retinoic acid suppresses growth of lesions, inhibits peritoneal cytokine secretion, and promotes macrophage differentiation in an immunocompetent mouse model of endometriosis,” Fertility and Sterility, vol. 97, no. 6, pp. 1430–1437, 2012.
- J. Rudzitis-Auth, C. Körbel, C. Scheuer, M. D. Menger, and M. W. Laschke, “Xanthohumol inhibits growth and vascularization of developing endometriotic lesions,” Human Reproduction, vol. 27, no. 6, pp. 1735–1744, 2012.
- M. W. Laschke, A. Elitzsch, C. Scheuer, J. H. Holstein, B. Vollmar, and M. D. Menger, “Rapamycin induces regression of endometriotic lesions by inhibiting neovascularization and cell proliferation,” British Journal of Pharmacology, vol. 149, no. 2, pp. 137–144, 2006.
- V. Mönckedieck, C. Sannecke, B. Husen et al., “Progestins inhibit expression of MMPs and of angiogenic factors in human ectopic endometrial lesions in a mouse model,” Molecular Human Reproduction, vol. 15, no. 10, pp. 633–643, 2009.
- Y. Katsuki, Y. Takano, Y. Futamura et al., “Effects of dienogest, a synthetic steroid, on experimental endometriosis in rats,” European Journal of Endocrinology, vol. 138, no. 2, pp. 216–226, 1998.
- F. Franzoni, A. Quiñones-Galvan, F. Regoli, E. Ferrannini, and F. Galetta, “A comparative study of the in vitro antioxidant activity of statins,” International Journal of Cardiology, vol. 90, no. 2-3, pp. 317–321, 2003.
- I. Sharma, V. Dhawan, N. Mahajan, S. C. Saha, and L. K. Dhaliwal, “In vitro effects of atorvastatin on lipopolysaccharide-induced gene expression in endometriotic stromal cells,” Fertility and Sterility, vol. 94, no. 5, pp. 1639–1646, 2010.
- N. Esfandiari, M. Khazaei, J. Ai et al., “Effect of a statin on an in vitro model of endometriosis,” Fertility and Sterility, vol. 87, no. 2, pp. 257–262, 2007.
- E. Novella-Maestre, C. Carda, I. Noguera et al., “Dopamine agonist administration causes a reduction in endometrial implants through modulation of angiogenesis in experimentally induced endometriosis,” Human Reproduction, vol. 24, no. 5, pp. 1025–1035, 2009.
- E. Novella-Maestre, C. Carda, A. Ruiz-Sauri, J. A. Garcia-Velasco, C. Simon, and A. Pellicer, “Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium: a novel molecular target for endometriosis therapy,” Biology of Reproduction, vol. 83, no. 5, pp. 866–873, 2010.
- F. Delgado-Rosas, R. Gómez, H. Ferrero et al., “The effects of ergot and non-ergot-derived dopamine agonists in an experimental mouse model of endometriosis,” Reproduction, vol. 142, no. 5, pp. 745–755, 2011.