{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:35:42Z","timestamp":1791920142080,"version":"4.3.4"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,11,18]],"date-time":"2015-11-18T00:00:00Z","timestamp":1447804800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,11,18]],"date-time":"2015-11-18T00:00:00Z","timestamp":1447804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>VEGF-A, an angiogenic factor, is increased in the peritoneal fluid of women with endometriosis. The cytokine TGF-\u03b21 is thought to play a role in the establishment of endometriosis lesions. Inhibitor of DNA binding (ID) proteins are transcriptional targets of TGF-\u03b21 and ID1 has been implicated in VEGF-A regulation during tumor angiogenesis. Herein, we determined whether peritoneal expression of VEGF-A is regulated by TGF-\u03b21 through the ID1 pathway in women with endometriosis. VEGF-A was measured in peritoneal fluid by ELISA (n\u2009=\u200916). VEGF-A and ID1 expression was examined in peritoneal biopsies (n\u2009=\u200913) and primary peritoneal and immortalized mesothelial cells (MeT5A) by immunohistochemistry, qRT-PCR and ELISA. VEGF-A was increased in peritoneal fluid from women with endometriosis and levels correlated with TGF-\u03b21 concentrations (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). VEGF-A was immunolocalized to peritoneal mesothelium and TGF-\u03b21 increased <jats:italic>VEGFA<\/jats:italic> mRNA (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) and protein (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) in mesothelial cells. ID1 was increased in peritoneum from women with endometriosis and TGF-\u03b21 increased concentrations of <jats:italic>ID1<\/jats:italic> mRNA (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) in mesothelial cells. VEGF-A regulation through ID1 was confirmed by siRNA in MeT5A cells (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). Our data supports role for ID1 in the pathophysiology of endometriosis, as an effector of TGF\u03b21 dependent upregulation of VEGF-A and highlights a novel potential therapeutic target.<\/jats:p>","DOI":"10.1038\/srep16859","type":"journal-article","created":{"date-parts":[[2015,11,18]],"date-time":"2015-11-18T10:27:11Z","timestamp":1447842431000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Peritoneal VEGF-A expression is regulated by TGF-\u03b21 through an ID1 pathway in women with endometriosis"],"prefix":"10.1038","volume":"5","author":[{"given":"Vicky J.","family":"Young","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed F.","family":"Ahmad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy K.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Colin","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew W.","family":"Horne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,11,18]]},"reference":[{"key":"BFsrep16859_CR1","doi-asserted-by":"publisher","first-page":"2389","DOI":"10.1056\/NEJMcp1000274","volume":"362","author":"LC Giudice","year":"2010","unstructured":"Giudice, L. C. Clinical practice. Endometriosis. The New England journal of medicine 362, 2389\u20132398, doi: 10.1056\/NEJMcp1000274 (2010).","journal-title":"The New England journal of medicine"},{"key":"BFsrep16859_CR2","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1093\/oxfordjournals.humrep.a137377","volume":"6","author":"TA Mahmood","year":"1991","unstructured":"Mahmood, T. A. & Templeton, A. Prevalence and genesis of endometriosis. Human reproduction 6, 544\u2013549 (1991).","journal-title":"Human reproduction"},{"key":"BFsrep16859_CR3","doi-asserted-by":"publisher","first-page":"g1752","DOI":"10.1136\/bmj.g1752","volume":"348","author":"M Hickey","year":"2014","unstructured":"Hickey, M., Ballard, K. & Farquhar, C. Endometriosis. Bmj 348, g1752, doi: 10.1136\/bmj.g1752 (2014).","journal-title":"Bmj"},{"key":"BFsrep16859_CR4","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1093\/humupd\/dmt024","volume":"19","author":"VJ Young","year":"2013","unstructured":"Young, V. J., Brown, J. K., Saunders, P. T. & Horne, A. W. The role of the peritoneum in the pathogenesis of endometriosis. Human reproduction update 19, 558\u2013569, doi: 10.1093\/humupd\/dmt024 (2013).","journal-title":"Human reproduction update"},{"key":"BFsrep16859_CR5","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1093\/humrep\/13.6.1686","volume":"13","author":"J Donnez","year":"1998","unstructured":"Donnez, J., Smoes, P., Gillerot, S., Casanas-Roux, F. & Nisolle, M. Vascular endothelial growth factor (VEGF) in endometriosis. Hum Reprod 13, 1686\u20131690 (1998).","journal-title":"Hum Reprod"},{"key":"BFsrep16859_CR6","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1093\/oxfordjournals.humrep.a019023","volume":"11","author":"J McLaren","year":"1996","unstructured":"McLaren, J., Prentice, A., Charnock-Jones, D. S. & Smith, S. K. Vascular endothelial growth factor (VEGF) concentrations are elevated in peritoneal fluid of women with endometriosis. Hum Reprod 11, 220\u2013223 (1996).","journal-title":"Hum Reprod"},{"key":"BFsrep16859_CR7","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1093\/humupd\/4.5.719","volume":"4","author":"W Kupker","year":"1998","unstructured":"Kupker, W., Schultze-Mosgau, A. & Diedrich, K. Paracrine changes in the peritoneal environment of women with endometriosis. Human reproduction update 4, 719\u2013723 (1998).","journal-title":"Human reproduction update"},{"key":"BFsrep16859_CR8","doi-asserted-by":"publisher","first-page":"3112","DOI":"10.1210\/jcem.81.8.8768883","volume":"81","author":"JL Shifren","year":"1996","unstructured":"Shifren, J. L. 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. The Journal of clinical endocrinology and metabolism 81, 3112\u20133118, doi: 10.1210\/jcem.81.8.8768883 (1996).","journal-title":"The Journal of clinical endocrinology and metabolism"},{"key":"BFsrep16859_CR9","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1172\/JCI118815","volume":"98","author":"J McLaren","year":"1996","unstructured":"McLaren, J. et al. Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. The Journal of clinical investigation 98, 482\u2013489, doi: 10.1172\/JCI118815 (1996).","journal-title":"The Journal of clinical investigation"},{"key":"BFsrep16859_CR10","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1093\/humupd\/6.1.45","volume":"6","author":"J McLaren","year":"2000","unstructured":"McLaren, J. Vascular endothelial growth factor and endometriotic angiogenesis. Human reproduction update 6, 45\u201355 (2000).","journal-title":"Human reproduction update"},{"key":"BFsrep16859_CR11","doi-asserted-by":"crossref","first-page":"329","DOI":"10.18388\/abp.2005_3446","volume":"52","author":"B Kaminska","year":"2005","unstructured":"Kaminska, B., Wesolowska, A. & Danilkiewicz, M. TGF beta signalling and its role in tumour pathogenesis. Acta biochimica Polonica 52, 329\u2013337 (2005).","journal-title":"Acta biochimica Polonica"},{"key":"BFsrep16859_CR12","doi-asserted-by":"publisher","first-page":"e106773","DOI":"10.1371\/journal.pone.0106773","volume":"9","author":"VJ Young","year":"2014","unstructured":"Young, V. J., Brown, J. K., Saunders, P. T., Duncan, W. C. & Horne, A. W. The peritoneum is both a source and target of TGF-beta in women with endometriosis. PloS one 9, e106773, doi: 10.1371\/journal.pone.0106773 (2014).","journal-title":"PloS one"},{"key":"BFsrep16859_CR13","doi-asserted-by":"publisher","first-page":"3450","DOI":"10.1210\/jc.2014-1026","volume":"99","author":"VJ Young","year":"2014","unstructured":"Young, V. J. et al. Transforming growth factor-beta induced Warburg-like metabolic reprogramming may underpin the development of peritoneal endometriosis. The Journal of clinical endocrinology and metabolism 99, 3450\u20133459, doi: 10.1210\/jc.2014-1026 (2014).","journal-title":"The Journal of clinical endocrinology and metabolism"},{"key":"BFsrep16859_CR14","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1159\/000067717","volume":"54","author":"A Pizzo","year":"2002","unstructured":"Pizzo, A. et al. Behaviour of cytokine levels in serum and peritoneal fluid of women with endometriosis. Gynecologic and obstetric investigation 54, 82\u201387, doi: 67717 (2002).","journal-title":"Gynecologic and obstetric investigation"},{"key":"BFsrep16859_CR15","first-page":"455","volume":"83","author":"N Chegini","year":"1994","unstructured":"Chegini, N., Gold, L. I. & Williams, R. S. Localization of transforming growth factor beta isoforms TGF-beta 1, TGF-beta 2 and TGF-beta 3 in surgically induced endometriosis in the rat. Obstetrics and gynecology 83, 455\u2013461 (1994).","journal-title":"Obstetrics and gynecology"},{"key":"BFsrep16859_CR16","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1023\/B:APPT.0000025804.25396.79","volume":"9","author":"YC Wong","year":"2004","unstructured":"Wong, Y. C., Wang, X. & Ling, M. T. Id-1 expression and cell survival. Apoptosis: an international journal on programmed cell death 9, 279\u2013289 (2004).","journal-title":"Apoptosis: an international journal on programmed cell death"},{"key":"BFsrep16859_CR17","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1002\/cbf.1799","volume":"29","author":"R Sun","year":"2011","unstructured":"Sun, R., Chen, W., Zhao, X., Li, T. & Song, Q. Acheron regulates vascular endothelial proliferation and angiogenesis together with Id1 during wound healing. Cell biochemistry and function 29, 636\u2013640, doi: 10.1002\/cbf.1799 (2011).","journal-title":"Cell biochemistry and function"},{"key":"BFsrep16859_CR18","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1093\/carcin\/bgi128","volume":"26","author":"MT Ling","year":"2005","unstructured":"Ling, M. T. et al. Overexpression of Id-1 in prostate cancer cells promotes angiogenesis through the activation of vascular endothelial growth factor (VEGF). Carcinogenesis 26, 1668\u20131676, doi: 10.1093\/carcin\/bgi128 (2005).","journal-title":"Carcinogenesis"},{"key":"BFsrep16859_CR19","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1038\/44334","volume":"401","author":"D Lyden","year":"1999","unstructured":"Lyden, D. et al. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 401, 670\u2013677, doi: 10.1038\/44334 (1999).","journal-title":"Nature"},{"key":"BFsrep16859_CR20","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1177\/089686080602600207","volume":"26","author":"S Yung","year":"2006","unstructured":"Yung, S., Li, F. K. & Chan, T. M. Peritoneal mesothelial cell culture and biology. Peritoneal dialysis international: journal of the International Society for Peritoneal Dialysis 26, 162\u2013173 (2006).","journal-title":"Peritoneal dialysis international: journal of the International Society for Peritoneal Dialysis"},{"key":"BFsrep16859_CR21","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1038\/ki.2013.217","volume":"84","author":"R Catar","year":"2013","unstructured":"Catar, R. et al. The proto-oncogene c-Fos transcriptionally regulates VEGF production during peritoneal inflammation. Kidney international 84, 1119\u20131128, doi: 10.1038\/ki.2013.217 (2013).","journal-title":"Kidney international"},{"key":"BFsrep16859_CR22","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1530\/rep.0.1230217","volume":"123","author":"R Gazvani","year":"2002","unstructured":"Gazvani, R. & Templeton, A. Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis. Reproduction 123, 217\u2013226 (2002).","journal-title":"Reproduction"},{"key":"BFsrep16859_CR23","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/S0962-8924(03)00147-8","volume":"13","author":"MB Ruzinova","year":"2003","unstructured":"Ruzinova, M. B. & Benezra, R. Id proteins in development, cell cycle and cancer. Trends in cell biology 13, 410\u2013418 (2003).","journal-title":"Trends in cell biology"},{"key":"BFsrep16859_CR24","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.molmed.2004.06.008","volume":"10","author":"S Fong","year":"2004","unstructured":"Fong, S., Debs, R. J. & Desprez, P. Y. Id genes and proteins as promising targets in cancer therapy. Trends in molecular medicine 10, 387\u2013392, doi: 10.1016\/j.molmed.2004.06.008 (2004).","journal-title":"Trends in molecular medicine"},{"key":"BFsrep16859_CR25","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/S1097-2765(03)00109-6","volume":"11","author":"Y Kang","year":"2003","unstructured":"Kang, Y., Chen, C. R. & Massague, J. A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Molecular cell 11, 915\u2013926 (2003).","journal-title":"Molecular cell"},{"key":"BFsrep16859_CR26","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1681\/ASN.2006030236","volume":"18","author":"Y Li","year":"2007","unstructured":"Li, Y., Yang, J., Luo, J. H., Dedhar, S. & Liu, Y. Tubular epithelial cell dedifferentiation is driven by the helix-loop-helix transcriptional inhibitor Id1. Journal of the American Society of Nephrology: JASN 18, 449\u2013460, doi: 10.1681\/ASN.2006030236 (2007).","journal-title":"Journal of the American Society of Nephrology: JASN"},{"key":"BFsrep16859_CR27","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1038\/cr.2008.321","volume":"19","author":"YY Liang","year":"2009","unstructured":"Liang, Y. Y., Brunicardi, F. C. & Lin, X. Smad3 mediates immediate early induction of Id1 by TGF-beta. Cell research 19, 140\u2013148, doi: 10.1038\/cr.2008.321 (2009).","journal-title":"Cell research"},{"key":"BFsrep16859_CR28","doi-asserted-by":"publisher","first-page":"8334","DOI":"10.1038\/sj.onc.1205160","volume":"20","author":"R Benezra","year":"2001","unstructured":"Benezra, R., Rafii, S. & Lyden, D. The Id proteins and angiogenesis. Oncogene 20, 8334\u20138341, doi: 10.1038\/sj.onc.1205160 (2001).","journal-title":"Oncogene"},{"key":"BFsrep16859_CR29","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1158\/1078-0432.CCR-07-1116","volume":"14","author":"R Tsunedomi","year":"2008","unstructured":"Tsunedomi, R. et al. Decreased ID2 promotes metastatic potentials of hepatocellular carcinoma by altering secretion of vascular endothelial growth factor. Clinical cancer research: an official journal of the American Association for Cancer Research 14, 1025\u20131031, doi: 10.1158\/1078-0432.CCR-07-1116 (2008).","journal-title":"Clinical cancer research: an official journal of the American Association for Cancer Research"},{"key":"BFsrep16859_CR30","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1677\/JOE-07-0419","volume":"196","author":"KS Fegan","year":"2008","unstructured":"Fegan, K. S., Rae, M. T., Critchley, H. O. & Hillier, S. G. Anti-inflammatory steroid signalling in the human peritoneum. The Journal of endocrinology 196, 369\u2013376, doi: 10.1677\/JOE-07-0419 (2008).","journal-title":"The Journal of endocrinology"},{"key":"BFsrep16859_CR31","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1016\/j.fertnstert.2014.07.1209","volume":"102","author":"A Fassbender","year":"2014","unstructured":"Fassbender, A. et al. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: IV. Tissue collection, processing and storage in endometriosis research. Fertility and sterility 102, 1244\u20131253, doi: 10.1016\/j.fertnstert.2014.07.1209 (2014).","journal-title":"Fertility and sterility"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep16859","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep16859.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep16859.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T18:56:52Z","timestamp":1672945012000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep16859"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11,18]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12,22]]}},"alternative-id":["BFsrep16859"],"URL":"https:\/\/doi.org\/10.1038\/srep16859","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,11,18]]},"assertion":[{"value":"13 July 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 October 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16859"}}