{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T13:45:00Z","timestamp":1791207900296,"version":"4.1.0"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2016,2,1]],"date-time":"2016-02-01T00:00:00Z","timestamp":1454284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":["rep.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Human chorionic gonadotropin (hCG) is a known trigger of ovarian hyperstimulation syndrome (OHSS), a potentially life-threatening complication of assisted reproduction. Administration of hCG results in the release of vascular endothelial growth factor (VEGF) from the ovary. We have previously shown that expression of pigment epithelium-derived factor (PEDF) in granulosa cell line is regulated by hCG, reciprocally to VEGF, and that the PEDF\u2013VEGF balance is impaired in OHSS. Our aim was to explore the signaling network by which hCG downregulates the expression of PEDF mRNA and protein in granulosa cells. We applied specific chemical inhibitors and stimuli to human primary granulosa cells and rat granulosa cell line. We found that PKA and protein kinase C, as well as EGFR, ERK1\/2 and PI3K, participate in the signaling network. The finding that hCG-induced PEDF downregulation and VEGF upregulation are mediated by similar signaling cascades emphasizes the delicate regulation of ovarian angiogenesis.<\/jats:p>","DOI":"10.1530\/rep-15-0478","type":"journal-article","created":{"date-parts":[[2015,11,26]],"date-time":"2015-11-26T21:48:41Z","timestamp":1448574521000},"page":"179-185","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":9,"title":["Pigment epithelium-derived factor regulation by human chorionic gonadotropin in granulosa cells"],"prefix":"10.1093","volume":"151","author":[{"given":"Hadas","family":"Bar-Joseph","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"},{"name":"IVF and Infertility Unit Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"},{"name":"Sackler Faculty of Medicine Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ido","family":"Ben-Ami","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"},{"name":"IVF and Infertility Unit Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"},{"name":"Sackler Faculty of Medicine Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Ron-El","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"},{"name":"IVF and Infertility Unit Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"},{"name":"Sackler Faculty of Medicine Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Shalgi","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"},{"name":"IVF and Infertility Unit Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"},{"name":"Sackler Faculty of Medicine Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Chuderland","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"},{"name":"IVF and Infertility Unit Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"},{"name":"Sackler Faculty of Medicine Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel 2 Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel 3 Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,2,1]]},"reference":[{"key":"2026010712432663300_bib1","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.drup.2009.12.001","article-title":"Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy","volume":"13","author":"Abdollahi","year":"2010","journal-title":"Drug Resistance Updates"},{"key":"2026010712432663300_bib2","doi-asserted-by":"crossref","first-page":"e81769","DOI":"10.1371\/journal.pone.0081769","article-title":"WNT3 inhibits cerebellar granule neuron progenitor proliferation and medulloblastoma formation via MAPK activation","volume":"8","author":"Anne","year":"2013","journal-title":"PLoS ONE"},{"key":"2026010712432663300_bib3","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/nrc3484","article-title":"The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential","volume":"13","author":"Becerra","year":"2013","journal-title":"Nature Reviews. Cancer"},{"key":"2026010712432663300_bib4","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1677\/joe.0.1670371","article-title":"Expression and localisation of vascular endothelial growth factor and basic fibroblast growth factor during the final growth of bovine ovarian follicles","volume":"167","author":"Berisha","year":"2000","journal-title":"Journal of Endocrinology"},{"key":"2026010712432663300_bib5","doi-asserted-by":"crossref","first-page":"19700","DOI":"10.3390\/ijms151119700","article-title":"Cell-surface receptors transactivation mediated by g protein-coupled receptors","volume":"15","author":"Cattaneo","year":"2014","journal-title":"International Journal of Molecular Sciences"},{"key":"2026010712432663300_bib6","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1093\/humrep\/dep432","article-title":"Signal mechanisms of vascular endothelial growth factor and interleukin-8 in ovarian hyperstimulation syndrome: dopamine targets their common pathways","volume":"25","author":"Chen","year":"2010","journal-title":"Human Reproduction"},{"key":"2026010712432663300_bib7","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1093\/humrep\/det027","article-title":"A physiological approach for treating endometriosis by recombinant pigment epithelium-derived factor (PEDF)","volume":"28","author":"Chuderland","year":"2013","journal-title":"Human Reproduction"},{"key":"2026010712432663300_bib8","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1517\/17460441.2013.794781","article-title":"The many facets of PEDF in drug discovery and disease: a diamond in the rough or split personality disorder?","volume":"8","author":"Craword","year":"2013","journal-title":"Expert Opinion on Drug Discovery"},{"key":"2026010712432663300_bib9","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1093\/molehr\/gan040","article-title":"HCG up-regulates hypoxia inducible factor-1 alpha in luteinized granulosa cells: implications for the hormonal regulation of vascular endothelial growth factor A in the human corpus luteum","volume":"14","author":"van den Driesche","year":"2008","journal-title":"Molecular Human Reproduction"},{"key":"2026010712432663300_bib10","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.bbrc.2004.09.129","article-title":"EGF-like factor epiregulin and amphiregulin expression is regulated by gonadotropins\/cAMP in human ovarian follicular cells","volume":"324","author":"Freimann","year":"2004","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"2026010712432663300_bib11","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1210\/jc.2011-0075","article-title":"Evidences for the existence of a low dopaminergic tone in polycystic ovarian syndrome: implications for OHSS development and treatment","volume":"96","author":"Gomez","year":"2011","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2026010712432663300_bib12","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1016\/j.fertnstert.2013.01.120","article-title":"Human chorionic gonadotropin controls luteal vascular permeability via vascular endothelial growth factor by down-regulation of a cascade of adhesion proteins","volume":"99","author":"Herr","year":"2013","journal-title":"Fertility and Sterility"},{"key":"2026010712432663300_bib13","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3109\/08977194.2011.607136","article-title":"Effect of heparin-binding EGF-like growth factor and amphiregulin on the MAP kinase-induced production of vascular endothelial growth factor by human granulosa cells","volume":"29","author":"Karakida","year":"2011","journal-title":"Growth Factors"},{"key":"2026010712432663300_bib14","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1080\/152165400410254","article-title":"Epidermal growth factor receptor signal transactivation","volume":"49","author":"Leserer","year":"2000","journal-title":"IUBMB Life"},{"key":"2026010712432663300_bib15","doi-asserted-by":"crossref","first-page":"2957","DOI":"10.1210\/endo-129-6-2957","article-title":"Epidermal growth factor elevates intracellular pH in chicken granulosa cells by activating protein kinase C","volume":"129","author":"Li","year":"1991","journal-title":"Endocrinology"},{"key":"2026010712432663300_bib16","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s00441-014-1953-2","article-title":"Snail regulated by PKC\/GSK-3beta pathway is crucial for EGF-induced epithelial-mesenchymal transition (EMT) of cancer cells","volume":"358","author":"Liu","year":"2014","journal-title":"Cell and Tissue Research"},{"key":"2026010712432663300_bib17","doi-asserted-by":"crossref","first-page":"e95910","DOI":"10.1371\/journal.pone.0095910","article-title":"Effect of antiprogesterone RU486 on VEGF expression and blood vessel remodeling on ovarian follicles before ovulation","volume":"9","author":"Mauro","year":"2014","journal-title":"PLoS ONE"},{"key":"2026010712432663300_bib18","first-page":"2867","article-title":"microRNA-125a-3p reduces cell proliferation and migration by targeting Fyn","volume":"126","author":"Ninio-Many","year":"2013","journal-title":"Journal of Cell Science"},{"key":"2026010712432663300_bib19","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1210\/me.2007-0246","article-title":"Luteinizing hormone signaling in preovulatory follicles involves early activation of the epidermal growth factor receptor pathway","volume":"22","author":"Panigone","year":"2008","journal-title":"Molecular Endocrinology"},{"key":"2026010712432663300_bib20","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1126\/science.1092463","article-title":"EGF-like growth factors as mediators of LH action in the ovulatory follicle","volume":"303","author":"Park","year":"2004","journal-title":"Science"},{"key":"2026010712432663300_bib21","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.2527\/1998.7661671x","article-title":"Expression of the angiogenic factors, basic fibroblast growth factor and vascular endothelial growth factor, in the ovary","volume":"76","author":"Reynolds","year":"1998","journal-title":"Journal of Animal Science"},{"key":"2026010712432663300_bib22","doi-asserted-by":"crossref","first-page":"2986","DOI":"10.1210\/endo.143.8.8976","article-title":"Acute signaling by the LH receptor is independent of protein kinase C activation","volume":"143","author":"Salvador","year":"2002","journal-title":"Endocrinology"},{"key":"2026010712432663300_bib23","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/BF02739060","article-title":"Establishment of an in vitro bioassay and radio receptor assay for LH\/CG in human sera using immortalized granulosa cells transfected with LH\/CG receptor","volume":"5","author":"Selvaraj","year":"1996","journal-title":"Endocrine"},{"key":"2026010712432663300_bib24","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1093\/humupd\/dmn008","article-title":"Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome","volume":"14","author":"Soares","year":"2008","journal-title":"Human Reproduction Update"},{"key":"2026010712432663300_bib25","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.mce.2008.07.011","article-title":"Identification of ERK and JNK as signaling mediators on protein kinase C activation in cultured granulosa cells","volume":"294","author":"Sriraman","year":"2008","journal-title":"Molecular and Cellular Endocrinology"},{"key":"2026010712432663300_bib26","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1083\/jcb.119.2.439","article-title":"Introduction of a gonadotropin receptor expression plasmid into immortalized granulosa cells leads to reconstitution of hormone-dependent steroidogenesis","volume":"119","author":"Suh","year":"1992","journal-title":"Journal of Cell Biology"},{"key":"2026010712432663300_bib27","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.4161\/cc.8.17.9471","article-title":"Towards a new understanding on the regulation of mammalian oocyte meiosis resumption","volume":"8","author":"Sun","year":"2009","journal-title":"Cell Cycle"},{"key":"2026010712432663300_bib28","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1530\/REP-06-0261","article-title":"Protein kinase C activity mediates LH-induced ErbB\/Erk signaling in differentiated hen granulosa cells","volume":"133","author":"Woods","year":"2007","journal-title":"Reproduction"}],"container-title":["Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rep.bioscientifica.com\/view\/journals\/rep\/151\/2\/179.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/reproduction\/article-pdf\/151\/2\/179\/64133075\/179.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/reproduction\/article-pdf\/151\/2\/179\/64133075\/179.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T17:44:02Z","timestamp":1767807842000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/reproduction\/article\/151\/2\/179\/8236142"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,2,1]]},"references-count":28,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2016,2,1]]}},"URL":"https:\/\/doi.org\/10.1530\/rep-15-0478","relation":{},"ISSN":["1470-1626","1741-7899"],"issn-type":[{"value":"1470-1626","type":"print"},{"value":"1741-7899","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,2,1]]},"published":{"date-parts":[[2016,2,1]]}}}