{"paper_id":"ba6bad5f-b273-410e-a334-da6fc5b65813","body_text":"Abstract\nEndometriosis is associated with local angiogenic and hypoxic mechanisms. Indeed, peritoneal fluid of women with endometriosis generates a specific microenvironment to support the growth and development of ectopic endometrial tissues. The association between proangiogenic markers and hypoxic processes in different endometriosis phenotypes was investigated in the present study, analyzing the expression of several genes, related to hypoxic signaling pathway and involved in angiogenic processes, in nonpregnant women with different forms of endometriosis. Samples of ovarian endometrioma (OMA; n = 16) or deep infiltrating endometriosis (DIE; n = 11) were collected, and in addition, control endometrium was collected from healthy women by hysteroscopy. The gene expression of the hypoxia-inducible factors (HIF) 1/2α, protease-activated receptors (PARs) ¼, and vascular endothelial growth factor (VEGF) A was evaluated by quantitative reverse-transcription polymerase chain reaction. Ovarian endometrioma expresses high levels of HIF-1/2α, PAR-1/4, and VEGF-A, while DIE did not show significantly different gene expression compared to endometrium from unaffected women. A positive correlation between the expression of HIF-1/2α and VEGF-A mRNA was observed in OMA. The overall data point out that the heterogeneity of the disease reflects differences in expression levels of genes associated with hypoxia and angiogenesis, suggesting that such conditions may have an active role in the development of the disease.\nSimilar content being viewed by others\nReferences\nPetraglia F, Arcuri F, de Ziegler D, Chapron C. Inflammation:a link between endometriosis and preterm birth. Fertil Steril. 2012; 98(1):36–40.\nStratton P, Berkley KJ. Chronic pelvic pain and endometriosis:translational evidence of the relationship and implications. Hum Reprod Update. 2011; 17(3):327–346.\nde Ziegler D, Borghese B, Chapron C. Endometriosis and infertility:pathophysiology and management. Lancet. 2010; 376(9742):730–738.\nLuZ, Zhang W, Jiang S, Zou J, Li Y. Effect of oxygen tensions on the proliferation and angiogenesis of endometriosis heterograft in severe combined immunodeficiency mice. Fertil Steril. 2014; 101(2):568–576.\nLin SC, Wang CC, Wu MH, Yang SH, Li YH, Tsai SJ. Hypoxia-induced microRNA-20a expression increases ERK phosphorylation and angiogenic gene expression in endometriotic stromal cells. J Clin Endocrinol Metab. 2012; 97(8):E1515–E1523.\nHsiao KY, Chang N, Lin SC, Li YH, Wu MH. Inhibition of dual specificity phosphatase-2 by hypoxia promotes interleukin-8-mediated angiogenesis in endometriosis. Hum Reprod. 2014; 29(12):2747–2755.\nKeith B, Johnson RS, Simon MC. HIFlalpha and HIF2alpha:sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2012; 12(1):9–22.\nZhang J, Salamonsen LA. Expression of hypoxia-inducible factors in human endometrium and suppression of matrix metallo-proteinases under hypoxic conditions do not support a major role for hypoxia in regulating tissue breakdown at menstruation. Hum Reprod. 2002; 17(2):265–274.\nGillies RM, Robinson SP, McPhail LD, Carter ND, Murray JF. Immunohistochemical assessment of intrinsic and extrinsic markers of hypoxia in reproductive tissue:differential expression of HIF lalpha and HIF2alpha in rat oviduct and endometrium. J Mol Histol. 2011; 42(4):341–354.\nKim BG, Yoo JY, Kim TH, et al. Aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling in endometriosis. Hum Reprod. 2015; 30(5):1069–1078.\nvan den Berg LL, Crane LM, van Oosten M, et al. Analysis of bio-marker expression in severe endometriosis and determination of possibilities for targeted intraoperative imaging. Int J Gynaecol Obstet. 2013; 121(1):35–40.\nGilabert-Estelles J, Ramon LA, Espana F, et al. Expression of angiogenic factors in endometriosis:relationship to fibrinolytic and metalloproteinase systems. Hum Reprod. 2007; 22(8):2120–2127.\nTsopanoglou NE, Pipili-Synetos E, Maragoudakis ME. Thrombin promotes angiogenesis by a mechanism independent of fibrin formation. Am J Physiol. 1993; 264(5 pt 1):C1302–C1307.\nHaralabopoulos GC, Grant DS, Kleinman HK, Maragoudakis ME. Thrombin promotes endothelial cell alignment in Matrigel in vitro and angiogenesis in vivo. Am J Physiol. 1997; 273(1pt 1):C239–C245.\nNaldini A, Carney DH, Pucci A, Pasquali A, Carraro F. Thrombin regulates the expression of proangiogenic cytokines via proteolytic activation of protease-activated receptor-1. Gen Pharmacol. 2000; 35(5):255–259.\nCoughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000; 407(6801):258–264.\nNaldini A, Morena E, Belotti D, Carraro F, AUavena P, Giavazzi R. Identification of thrombin-like activity in ovarian cancer associated ascites and modulation of multiple cytokine networks. Thromb Haemost. 2011; 106(4):705–711.\nNaldini A, Bernini C, Pucci A, Carraro F. Thrombin-mediated IL-10 up-regulation involves protease-activated receptor (PAR)-1 expression in human mononuclear leukocytes. J Leukoc Biol. 2005; 78(3):736–744.\nNaldini A, Filippi I, Ardinghi C, Silini A, Giavazzi R, Carraro F. Identification of a functional role for the protease-activated receptor-1 in hypoxic breast cancer cells. Eur J Cancer. 2009; 45(3):454–460.\nOsuga Y, Hirota Y, Yoshino O, Hirata T, Koga K, Taketani Y. Proteinase-activated receptors in the endometrium and endometriosis. Front Biosci (Schol Ed). 2012; 4:1201–1212.\nHirota Y, Osuga Y, Hirata T, et al. Possible involvement of thrombin/protease-activated receptor I system in the pathogenesis of endometriosis. J Clin Endocrinol Metab. 2005; 90(6):3673–3679.\nLin M, Weng H, Wang X, Zhou B, Yu P, Wang Y. The role of tissue factor and protease-activated receptor 2 in endometriosis. Am J Reprod Immunol. 2012; 68(3):251–257.\nGoteri G, Lucarini G, Zizzi A, et al. Proangiogenetic molecules, hypoxia-inducible factor-1alpha and nitric oxide synthase iso-forms in ovarian endometriotic cysts. Virchows Arch. 2010; 456(6):703–710.\nLockwood CJ, Krikun G, Koo AB, Kadner S, Schatz F. Differential effects of thrombin and hypoxia on endometrial stromal and glandular epithelial cell vascular endothelial growth factor expression. J Clin Endocrinol Metab. 2002; 87(9):4280–4286.\nExacoustos C, Malzoni M, Di Giovanni A, et al. Ultrasound mapping system for the surgical management of deep infiltrating endometriosis. Fertil Steril. 2014; 102(1):143–150.\nAbrao MS, Petraglia F, Falcone T, Keckstein J, Osuga Y, Chapron C. Deep endometriosis infiltrating the recto-sigmoid:critical factors to consider before management. Hum Reprod Update. 2015; 21(3):329–339.\nRevised American Fertility Society classification of endometriosis: 19S5. Fertil Steril. 1985; 43(3):351–352.\nVandesompele J, De PK, Pattyn F, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3(7):0034.\nBecker CM, Rohwer N, Funakoshi T, et al. 2-methoxyestradiol inhibits hypoxia-inducible factor-1 {alpha} and suppresses growth of lesions in a mouse model of endometriosis. Am J Pathol. 2008; 172(2):534–544.\nNisoUe M, Casanas-Roux F, Anaf V, Mine JM, Donnez J. Mor-phometric study of the stromal vascularization in peritoneal endometriosis. Fertil Steril. 1993; 59(3):681–684.\nMahutte NG, Matalliotakis IM, Goumenou AG, Vassiliadis S, Koumantakis GE, Ariel A. Inverse correlation between peritoneal fluid leptin concentrations and the extent of endometriosis. Hum Reprod. 2003; 18(6):1205–1209.\nNakanishi-Matsui M, Zheng YW, Sulciner DJ, Weiss EJ, Lude-man MJ, Coughlin SR. PAR3 is a cofactor for PAR4 activation by thrombin. Nature. 2000; 404(6778):609–613.\nShapiro MJ, Weiss EJ, Faruqi TR, Coughlin SR. Protease-activated receptors I and 4 are shut off with distinct kinetics after activation by thrombin. J Biol Chem. 2000; 275(33):25216–25221.\nWang Y, Lin M, Weng H, Wang X, Yang L, Liu F. ENMD-1068, a protease-activated receptor 2 antagonist, inhibits the development of endometriosis in a mouse model. Am J Obstet Gynecol. 2014; 210(6):531–538.\nAllavena G, Carrarelli P, Del BB, Luisi S, Petraglia F, Maellaro E3. Autophagy is upregulated in ovarian endometriosis:a possible interplay with p53 and heme oxygenase-1. Fertil Steril. 2015; 103(5):1244–1251.\nBorghese B, Mondon F, Noel JC, et al. Gene expression profile for ectopic versus eutopic endometrium provides new insights into endometriosis oncogenic potential. Mol Endocrinol. 2008; 22(11):2557–2562.\nTosti C, Pinzauti S, SantuUi P, Chapron C, Petraglia F. Pathogenetic mechanisms of deep infiltrating endometriosis. Reprod Sci. 2015; 22(9):1053–1059.\nAuthor information\nAuthors and Affiliations\nCorresponding author\nRights and permissions\nAbout this article\nCite this article\nFilippi, I., Carrarelli, P., Luisi, S. et al. Different Expression of Hypoxic and Angiogenic Factors in Human Endometriotic Lesions. Reprod. Sci. 23, 492–497 (2016). https://doi.org/10.1177/1933719115607978\nPublished:\nIssue date:\nDOI: https://doi.org/10.1177/1933719115607978","source_license":"CC0","license_restricted":false}