High Lymph Vessel Density and Expression of Lymphatic Growth Factors in Peritoneal Endometriosis

To investigate the occurrence of lymph vessels and lymphangiogenic growth factors in peritoneal lesions, we performed immunohistochemical staining of peritoneal lesions of 37 patients with antibodies against podoplanin (D2-40), lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), prospero homeobox protein 1 (Prox-1), vascular epithelial growth factor (VEGF)-C/VEGF-D. Overall, 10 lesions were double stained against D2-40 and von Willebrand factor. The lymph vessel density in peritoneal lesion was significantly higher in comparison with healthy peritoneum. All lymph vessel makers could be detected, whereby the lymph vessel density of LYVE-1- and Prox-1-positive lymph vessels was significantly higher than the lymph vessel density of D2-40-positive lymph vessels. Endometriotic epithelial cells and stromal cells (SCs) showed a moderate-to-strong VEGF-C/VEGF-D expression. The VEGF-C-/VEGF-D-positive macrophages in endometriotic SCs could be observed. The lymphatic vasculature seems to form a further component of peritoneal lesions and could be involved in the inflammatory process. These data demonstrated a further step in the clarification of the pathogenesis of endometriosis. Similar content being viewed by others

Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279. Anaf V, Simon P, Fayt I, Noel J. Smooth muscles are frequent components of endometriotic lesions. Hum Reprod. 2000;15(4): 767–771. Mechsner S, Bartley J, Loddenkemper C, Salomon DS, Starzinski-Powitz A, Ebert AD. Oxytocin receptor expression in smooth muscle cells of peritoneal endometriotic lesions and ovarian endometriotic cysts. Fertil Steril. 2005;83(suppl 1):1220–1231. Taylor RN, Lebovic DI, Mueller MD. Angiogenic factors in endometriosis. Ann N Y Acad Sci. 2002;955:89–100; Volume 955, ENDOMETRIOSIS: EMERGING RESEARCH AND INTERVENTION STRATEGIES, 89–100, March 2002. Groothuis PG, Nap AW, Winterhager E, Grummer R. Vascular development in endometriosis. Angiogenesis. 2005;8(2): 147–156. Tokushige N, Markham R, Russell P, Fraser IS. Nerve fibres in peritoneal endometriosis. Hum Reprod. 2006;21(11): 3001–3007. Mechsner S, Schwarz J, Thode J, Loddenkemper C, Salomon DS, Ebert AD. Growth-associated protein 43-positive sensory nerve fibers accompanied by immature vessels are located in or near peritoneal endometriotic lesions. Fertil Steril. 2007;88(3): 581–587. Barcena de Arellano ML, Arnold J, Vercellino F, Chiantera V, Schneider A, Mechsner S. Overexpression of nerve growth factor in peritoneal fluid from women with endometriosis may promote neurite outgrowth in endometriotic lesions. Fertil Steril. 2010; 95(3):1123–1126. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447): 1789–1799. Donoghue JF, Lederman FL, Susil BJ, Rogers PA. Lymphangio-genesis of normal endometrium and endometrial adenocarcinoma. Hum Reprod. 2007;22(6):1705–1713. Rogers PA, Donoghue JF, Walter LM, Girling JE. Endometrial angiogenesis, vascular maturation, and lymphangiogenesis. Reprod Sci. 2009;16(2):147–151. Paavonen K, Mandelin J, Partanen T, et al. Vascular endothelial growth factors C and D and their VEGFR-2 and 3 receptors in blood and lymphatic vessels in healthy and arthritic synovium. J Rheumatol. 2002;29(l):39–45. Kunstfeld R, Hirakawa S, Hong YK, et al. Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia. Blood. 2004;104(4):1048–1057. Kajiya K, Hirakawa S, Detmar M. Vascular endothelial growth factor-A mediates ultraviolet B-induced impairment of lymphatic vessel function. Am J Pathol. 2006;169(4):1496–1503. Pedica F, Ligorio C, Tonelli P, Bartolini S, Baccarini P. Lymphangiogenesis in Crohn's disease: an immunohistochemical study using monoclonal antibody D2-40. Virchows Arch. 2008; 452(l):57–63. Geleff S, Schoppmann SF, Oberhuber G. Increase in podoplanin-expressing intestinal lymphatic vessels in inflammatory bowel disease. Virchows Arch. 2003;442(3):231–237. Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K. Lymphangiogenesis and cancer metastasis. Nat Rev Cancer. 2002; 2(8):573–583. Karkkainen MJ, Haiko P, Sainio K, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 2004;5(l):74–80. Breiteneder-Geleff S, Soleiman A, Kowalski H, et al. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol. 1999;154(2):385-394. Schacht V, Dadras SS, Johnson LA, Jackson DG, Hong YK, Detmar M. Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. Am J Pathol. 2005; 166(3):913–921. Banerji S, Ni J, Wang SX, et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol. 1999;144(4):789–801. Wilting J, Papoutsi M, Christ B, et al. The transcription factor Proxl is a marker for lymphatic endothelial cells in normal and diseased human tissues. Faseb J. 2002;16(10):1271–1273. Medicine ASfR. Revised American society for reproductive medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817–821. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogen-esis and metastasis—correlation in invasive breast carcinoma. N Engl J Med. 1991;324(l):l–8. Nisolle M, Casanas-Roux F, Anaf V, Mine JM, Donnez J. Morphometric study of the stromal vascularization in peritoneal endometriosis. Fertil Steril. 1993;59(3):681–684. Matsuzaki S, Canis M, Darcha C, Dechelotte P, Pouly JL, Bruhat MA. Angiogenesis in endometriosis. Gynecol Obstet Invest. 1998;46(2):111–115. Matsuzaki S, Canis M, Murakami T, Dechelotte P, Bruhat MA, Okamura K. Immunohistochemical analysis of the role of angiogenic status in the vasculature of peritoneal endometriosis. Fertil Steril. 2001;76(4):712–716. Bourlev V, Volkov N, Pavlovitch S, Lets N, Larsson A, Olovsson M. The relationship between microvessel density, proliferative activity and expression of vascular endothelial growth factor-A and its receptors in eutopic endometrium and endometriotic lesions. Reproduction. 2006;132(3):501–509. Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol. 1927;3(2):93–110, 143. Javert CT. Pathogenesis of endometriosis based on endometrial homeoplasia, direct extension, exfoliation and implantation, lymphatic and hematogenous metastasis, including five case reports of endometrial tissue in pelvic lymph nodes. Cancer. 1949;2(3): 399–410. Ueki M. Histologic study of endometriosis and examination of lymphatic drainage in and from the uterus. Am J Obstet Gynecol. 1991;165(l):201–209. Sleeman JP, Krishnan J, Kirkin V, Baumann P. Markers for the lymphatic endothelium: in search of the holy grail? Microsc Res Tech. 2001;55(2):61–69. Van der Auwera I, Cao Y, Tille JC, et al. First international consensus on the methodology of lymphangiogenesis quantification in solid human tumours. Br J Cancer. 2006;95(12):1611–1625. Oliver G. Lymphatic vasculature development. Nat Rev Immunol. 2004;4(l):35–45. Petrova TV, Makinen T, Makela TP, et al. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. Embo J. 2002;21(17): 4593–4599. Hong YK, Harvey N, Noh YH, et al. Proxl is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn. 2002;225(3):351–357. Schacht V, Ramirez MI, Hong YK, et al. Tlalpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. Embo J. 2003;22(14):3546–3556. Karkkainen MJ, Petrova TV. Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene. 2000;19(49):5598–5605. Choi WW, Lewis MM, Lawson D, et al. Angiogenic and lym-phangiogenic microvessel density in breast carcinoma: correlation with clinicopathologic parameters and VEGF-family gene expression. Mod Pathol. 2005;18(1):143–152. Gombos Z, Xu X, Chu CS, Zhang PJ, Acs G. Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix. Clin Cancer Res. 2005;11(23):8364–8371. Fan YZ, Li GM, Huang GP, Li XP. [Clinical significance of detection on lymphatic microvessel, lymphatic microvessel density and vascular endothelial growth factor-C in patients with colorectal carcinoma]. Zhonghua Wei Chang Wai Ke Za Zhi. 2006; 9(6):477–482. Schoppmann SF, Birner P, Stockl J, et al. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol. 2002;161(3):947–956. Schoppmann SF, Fenzl A, Nagy K, et al. VEGF-C expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival. Surgery. 2006; 139(6):839–846. Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril. 2001 ;75(1): 1–10. Wu MY, Ho HN. The role of cytokines in endometriosis. Am J Reprod Immunol. 2003;49(5):285–296. Ristimaki A, Narko K, Enholm B, Joukov V, Alitalo K. Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C. J Biol Chem. 1998;273(14):8413–8418. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Reichelt, U., Keichel, S., de Arellano, M.L.B. et al. High Lymph Vessel Density and Expression of Lymphatic Growth Factors in Peritoneal Endometriosis. Reprod. Sci. 19, 876–882 (2012). https://doi.org/10.1177/1933719112438440 Published: Issue date: DOI: https://doi.org/10.1177/1933719112438440