{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T18:51:38Z","timestamp":1774896698037,"version":"3.50.1"},"reference-count":63,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Robert H. Smith Faculty of Agriculture, Food and Environment Research Fund for International Cooperation scholarship","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"e German-Israeli Foundation for Scientific Research 379 and Development (GIF)","award":["I-1417"],"award-info":[{"award-number":["I-1417"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Granulosa-lutein cells (GLCs) from PCOS women display reduced HIF-1\u03b1 and EDN2 levels, suggesting their role in PCOS etiology. Here, we investigated the mechanisms involved in aberrant EDN2 expression in PCOS, and its association with HIF-1\u03b1. Various HIF-1\u03b1-dependent factors were studied in GLCs from PCOS and compared to normally ovulating women. MicroRNA-210 (miR-210), its target genes (SDHD and GPD1L), and HIF-1\u03b1-responsive genes (EDN2 and VEGFA) differed in GLCs from PCOS, compared with those of healthy women. Levels of miR-210\u2014designated hypoxiamiR\u2014and EDN2 were reduced in the PCOS GLCs; concomitantly, GPD1L and SDHD levels were elevated. Cultured GLCs retained low EDN2 expression and had low HIF-1\u03b1 levels, providing evidence for a disrupted hypoxic response in the PCOS GLCs. However, VEGFA expression was elevated in these cells. Next, miR-210 levels were manipulated. miR-210-mimic stimulated EDN2 twice as much as the miR-NC-transfected cells, whereas miR-210-inhibitor diminished EDN2, emphasizing the importance of hypoxiamiR for EDN2 induction. Intriguingly, VEGFA transcripts were reduced by both miR-210-mimic and -inhibitor, demonstrating that EDN2 and VEGFA are distinctly regulated. Disrupted hypoxic response in the GLCs of periovulatory follicles in PCOS women may play a role in ovulation failure, and in the reduced fertility prevalent in this syndrome.<\/jats:p>","DOI":"10.3390\/ijms22158216","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T12:59:24Z","timestamp":1627649964000},"page":"8216","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Reduced Endothelin-2 and Hypoxic Signaling Pathways in Granulosa-Lutein Cells of PCOS Women"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7159-2256","authenticated-orcid":false,"given":"Magdalena","family":"Szymanska","sequence":"first","affiliation":[{"name":"Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, Israel"},{"name":"Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences, Tuwima 10, 10-748 Olsztyn, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ketan","family":"Shrestha","sequence":"additional","affiliation":[{"name":"Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, Israel"},{"name":"UK Medical Center, Department of Obstetrics and Gynecology, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eliezer","family":"Girsh","sequence":"additional","affiliation":[{"name":"Fertility and IVF Unit, Barzilai University Medical Center, Ashkelon 7830604, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Avi","family":"Harlev","sequence":"additional","affiliation":[{"name":"Fertility and IVF Unit, Barzilai University Medical Center, Ashkelon 7830604, Israel"},{"name":"Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iris","family":"Eisenberg","sequence":"additional","affiliation":[{"name":"The Magda and Richard Hoffman Center for Human Placenta Research, Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem 91240, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8583-1596","authenticated-orcid":false,"given":"Tal","family":"Imbar","sequence":"additional","affiliation":[{"name":"The Magda and Richard Hoffman Center for Human Placenta Research, Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem 91240, Israel"},{"name":"Hadassah Ein Kerem Medical Center, Fertility Preservation Unit, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6727-6787","authenticated-orcid":false,"given":"Rina","family":"Meidan","sequence":"additional","affiliation":[{"name":"Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1097\/AOG.0000000000002698","article-title":"Polycystic Ovary Syndrome","volume":"132","author":"Azziz","year":"2018","journal-title":"Obstet. Gynecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1677\/jme.0.0330059","article-title":"The molecular characteristics of polycystic ovary syndrome (PCOS) ovary defined by human ovary cDNA microarray","volume":"33","author":"Diao","year":"2004","journal-title":"J. Mol. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"The Rotterdam ESHRE\/ASRM-Sponsored PCOS Consensus Workshop Group (2004). 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