title: Comprehensive study of angiogenic factors in women with endometriosis compared to women without endometriosis.
abstract: OBJECTIVE
  Endometriosis is a benign gynaecological disease, affecting women during their reproductive years. Angiogenesis represents a crucial step in the pathogenesis of endometriosis, because endometriotic lesions require neovascularization. In this study several angiogenesis-related genes have been studied in the context of endometriosis. Some of the analyzed angiogenic factors as well as their interactions were studied the first time regarding a possible association with endometriosis.
  
  
  METHODS
  This case-control study consisted of 205 biopsies of 114 patients comprising 61 endometriosis patients and 53 control patients. Among them in 29 cases paired samples were obtained. VEGFA, VEGFR2, HIF1A, HGF, NRP1, PDGFB, FGF18, TNFα, TGFB2, EPHB4, EPO and ANG mRNA expression was analyzed by qRT-PCR in ectopic tissue samples, in eutopic endometrium of women with and without endometriosis, and in unaffected peritoneum of women with and without endometriosis.
  
  
  RESULTS
  VEGFR2, HIF1A, HGF, PDGFB, NRP1 and EPHB4 are overexpressed in ectopic lesions compared to eutopic tissues. VEGFR2, HGF, PDGFB, NRP1, and EPHB4 showed highest mRNA levels in peritoneal implants, in contrast HIF1A showed the highest expression in ovarian endometriomas. Correlation analyses of angiogenic factors in ectopic lesions revealed the strongest associations between VEGFR2, PDGFB, and EPHB4. We further showed a significant upregulation of VEGFR2, HIF1A and EPHB4 in eutopic endometrium of women with endometriosis compared to that of controls and a trend towards upregulation of HGF. Additionally, a significant downregulation for HIF1A, HGF and EPHB4 was observed in unaffected peritoneal tissues of women with endometriosis compared to controls.
  
  
  CONCLUSIONS
  We identified new genes (EPHB4 and NRP1) that may contribute to angiogenesis in endometriosis beside known factors (VEGFA, VEGFR2, HIF1A, HGF, and PDGFB). Correlation studies revealed the putative importance of EBHB4 in association with endometriosis. Our analyses support preliminary reports that angiogenic factors seem to be differently expressed in peritoneal implants, ovarian endometriomas and deep infiltrating endometriosis. Our observation that angiogenic factors are differently expressed in the unaffected peritoneum of women with endometriosis compared to women without endometriosis underlines the importance of the peritoneum in the establishment of endometriosis.
authors.affiliation: Department of Obstetric and Gynecology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria(​); Fetal Medicine Research Institute, King's College Hospital, 16-20 Windsor Walk, Denmark Hill, London SE58B, United Kingdom. Electronic address: guelen.yerlikaya@meduniwien.ac.at.
authors.forename: Gülen
authors.initials: G
authors.lastname: Yerlikaya
authors.affiliation: Clinical Institute of Pathology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Electronic address: surkithini.balendran@meduniwien.ac.at.
authors.forename: Sukirthini
authors.initials: S
authors.lastname: Balendran
authors.affiliation: Department of Obstetric and Gynecology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria(​). Electronic address: Katharina.proestling@meduniwien.ac.at.
authors.forename: Katharina
authors.initials: K
authors.lastname: Pröstling
authors.affiliation: Department of Obstetric and Gynecology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria(​). Electronic address: theresa.reischer@meduniwien.ac.at.
authors.forename: Theresa
authors.initials: T
authors.lastname: Reischer
authors.affiliation: Clinical Institute of Pathology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Electronic address: peter.birner@meduniwien.ac.at.
authors.forename: Peter
authors.initials: P
authors.lastname: Birner
authors.affiliation: Department of Obstetric and Gynecology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria(​). Electronic address: rene.wenzl@meduniwien.ac.at.
authors.forename: Rene
authors.initials: R
authors.lastname: Wenzl
authors.affiliation: Department of Obstetric and Gynecology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria(​). Electronic address: Lorenz.kuessel@meduniwien.ac.at.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Kuessel
authors.affiliation: Clinical Institute of Pathology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. Electronic address: berthold.streubel@meduniwien.ac.at.
authors.forename: Berthold
authors.initials: B
authors.lastname: Streubel
authors.affiliation: Department of Obstetric and Gynecology, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria(​). Electronic address: heinrich.husslein@meduniwien.ac.at.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Husslein
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D004715:Endometriosis / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism* / Q000473:pathology; D004921:Erythropoietin / Q000378:metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D039942:Neuropilin-1 / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D036224:Receptor, EphB4 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: C066855:HGF protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020574:Proto-Oncogene Proteins c-sis; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C113569:fibroblast growth factor 18; D004921:Erythropoietin; D039942:Neuropilin-1; D005346:Fibroblast Growth Factors; D017228:Hepatocyte Growth Factor; C000588866:KDR protein, human; D036224:Receptor, EphB4; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenic factors; Endometriosis; Gene expression; Peritoneum