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.
BulunSE. Endometriosis. N Engl J Med. 2009;360(3):268–279.
2.
AnafVSimonPFaytINoelJ. Smooth muscles are frequent components of endometriotic lesions. Hum Reprod. 2000;15(4):767–771.
3.
MechsnerSBartleyJLoddenkemperCSalomonDSStarzinski-PowitzAEbertAD. Oxytocin receptor expression in smooth muscle cells of peritoneal endometriotic lesions and ovarian endometriotic cysts. Fertil Steril. 2005;83(suppl 1):1220–1231.
4.
TaylorRNLebovicDIMuellerMD. 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.
5.
GroothuisPGNapAWWinterhagerEGrummerR. Vascular development in endometriosis. Angiogenesis. 2005;8(2):147–156.
6.
TokushigeNMarkhamRRussellPFraserIS. Nerve fibres in peritoneal endometriosis. Hum Reprod. 2006;21(11):3001–3007.
7.
MechsnerSSchwarzJThodeJLoddenkemperCSalomonDSEbertAD. 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.
8.
Barcena de ArellanoMLArnoldJVercellinoFChianteraVSchneiderAMechsnerS. 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.
DonoghueJFLedermanFLSusilBJRogersPA. Lymphangiogenesis of normal endometrium and endometrial adenocarcinoma. Hum Reprod. 2007;22(6):1705–1713.
11.
RogersPADonoghueJFWalterLMGirlingJE. Endometrial angiogenesis, vascular maturation, and lymphangiogenesis. Reprod Sci. 2009;16(2):147–151.
12.
PaavonenKMandelinJPartanenTVascular 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(1):39–45.
13.
KunstfeldRHirakawaSHongYKInduction 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.
14.
KajiyaKHirakawaSDetmarM. Vascular endothelial growth factor-A mediates ultraviolet B-induced impairment of lymphatic vessel function. Am J Pathol. 2006;169(4):1496–1503.
15.
PedicaFLigorioCTonelliPBartoliniSBaccariniP. Lymphangiogenesis in Crohn's disease: an immunohistochemical study using monoclonal antibody D2-40. Virchows Arch. 2008;452(1):57–63.
16.
GeleffSSchoppmannSFOberhuberG. Increase in podoplanin-expressing intestinal lymphatic vessels in inflammatory bowel disease. Virchows Arch. 2003;442(3):231–237.
17.
StackerSAAchenMGJussilaLBaldwinMEAlitaloK. Lymphangiogenesis and cancer metastasis. Nat Rev Cancer. 2002;2(8):573–583.
18.
KarkkainenMJHaikoPSainioKVascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 2004;5(1):74–80.
19.
Breiteneder-GeleffSSoleimanAKowalskiHAngiosarcomas 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.
20.
SchachtVDadrasSSJohnsonLAJacksonDGHongYKDetmarM. 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.
21.
BanerjiSNiJWangSXLYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol. 1999;144(4):789–801.
22.
WiltingJPapoutsiMChristBThe transcription factor Prox1 is a marker for lymphatic endothelial cells in normal and diseased human tissues. Faseb J. 2002;16(10):1271–1273.
23.
. Medicine ASfR. Revised American society for reproductive medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817–821.
24.
WeidnerNSempleJPWelchWRFolkmanJ. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med. 1991;324(1):1–8.
25.
NisolleMCasanas-RouxFAnafVMineJMDonnezJ. Morphometric study of the stromal vascularization in peritoneal endometriosis. Fertil Steril. 1993;59(3):681–684.
26.
MatsuzakiSCanisMDarchaCDechelottePPoulyJLBruhatMA. Angiogenesis in endometriosis. Gynecol Obstet Invest. 1998;46(2):111–115.
27.
MatsuzakiSCanisMMurakamiTDechelottePBruhatMAOkamuraK. Immunohistochemical analysis of the role of angiogenic status in the vasculature of peritoneal endometriosis. Fertil Steril. 2001;76(4):712–716.
28.
BourlevVVolkovNPavlovitchSLetsNLarssonAOlovssonM. 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.
29.
SampsonJA. 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.
30.
JavertCT. 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.
31.
UekiM. Histologic study of endometriosis and examination of lymphatic drainage in and from the uterus. Am J Obstet Gynecol. 1991;165(1):201–209.
32.
SleemanJPKrishnanJKirkinVBaumannP. Markers for the lymphatic endothelium: in search of the holy grail?Microsc Res Tech. 2001;55(2):61–69.
33.
Van der AuweraICaoYTilleJCFirst international consensus on the methodology of lymphangiogenesis quantification in solid human tumours. Br J Cancer. 2006;95(12):1611–1625.
PetrovaTVMakinenTMakelaTPLymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. Embo J. 2002;21(17):4593–4599.
36.
HongYKHarveyNNohYHProx1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn. 2002;225(3):351–357.
37.
SchachtVRamirezMIHongYKT1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. Embo J. 2003;22(14):3546–3556.
38.
KarkkainenMJPetrovaTV. Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene. 2000;19(49):5598–5605.
39.
ChoiWWLewisMMLawsonDAngiogenic and lymphangiogenic microvessel density in breast carcinoma: correlation with clinicopathologic parameters and VEGF-family gene expression. Mod Pathol. 2005;18(1):143–152.
40.
GombosZXuXChuCSZhangPJAcsG. 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.
41.
FanYZLiGMHuangGPLi 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.
42.
SchoppmannSFBirnerPStocklJTumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol. 2002;161(3):947–956.
43.
SchoppmannSFFenzlANagyKVEGF-C expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival. Surgery. 2006;139(6):839–846.
44.
LebovicDIMuellerMDTaylorRN. Immunobiology of endometriosis. Fertil Steril. 2001;75(1):1–10.
45.
WuMYHoHN. The role of cytokines in endometriosis. Am J Reprod Immunol. 2003;49(5):285–296.
46.
RistimakiANarkoKEnholmBJoukovVAlitaloK. Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C. J Biol Chem. 1998;273(14):8413–8418.
