Reduced Endothelin-2 and Hypoxic Signaling Pathways in Granulosa-Lutein Cells of PCOS Women
Granulosa-lutein cells (GLCs) from PCOS women display reduced <i>HIF-1α</i> and <i>EDN2</i> levels, suggesting their role in PCOS etiology. Here, we investigated the mechanisms involved in aberrant <i>EDN2</i> expression in PCOS, and its association with <i>...
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MDPI AG
2021-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/15/8216 |
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| author | Magdalena Szymanska Ketan Shrestha Eliezer Girsh Avi Harlev Iris Eisenberg Tal Imbar Rina Meidan |
| author_facet | Magdalena Szymanska Ketan Shrestha Eliezer Girsh Avi Harlev Iris Eisenberg Tal Imbar Rina Meidan |
| author_sort | Magdalena Szymanska |
| collection | DOAJ |
| description | Granulosa-lutein cells (GLCs) from PCOS women display reduced <i>HIF-1α</i> and <i>EDN2</i> levels, suggesting their role in PCOS etiology. Here, we investigated the mechanisms involved in aberrant <i>EDN2</i> expression in PCOS, and its association with <i>HIF-1α</i>. Various <i>HIF-1α</i>-dependent factors were studied in GLCs from PCOS and compared to normally ovulating women. MicroRNA-210 (miR-210), its target genes (<i>SDHD</i> and <i>GPD1L</i>), and <i>HIF-1α</i>-responsive genes (<i>EDN2</i> and <i>VEGFA</i>) differed in GLCs from PCOS, compared with those of healthy women. Levels of miR-210—designated hypoxiamiR—and <i>EDN2</i> were reduced in the PCOS GLCs; concomitantly, <i>GPD1L</i> and <i>SDHD</i> levels were elevated. Cultured GLCs retained low <i>EDN2</i> expression and had low <i>HIF-1α</i> levels, providing evidence for a disrupted hypoxic response in the PCOS GLCs. However, <i>VEGFA</i> expression was elevated in these cells. Next, miR-210 levels were manipulated. miR-210-mimic stimulated <i>EDN2</i> twice as much as the miR-NC-transfected cells, whereas miR-210-inhibitor diminished <i>EDN2,</i> emphasizing the importance of hypoxiamiR for <i>EDN2</i> induction. Intriguingly, <i>VEGFA</i> transcripts were reduced by both miR-210-mimic and -inhibitor, demonstrating that <i>EDN2</i> and <i>VEGFA</i> 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. |
| first_indexed | 2024-03-10T09:14:09Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T09:14:09Z |
| publishDate | 2021-07-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-827a122fa9ca4f3489087a303156f9092023-11-22T05:45:03ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-012215821610.3390/ijms22158216Reduced Endothelin-2 and Hypoxic Signaling Pathways in Granulosa-Lutein Cells of PCOS WomenMagdalena Szymanska0Ketan Shrestha1Eliezer Girsh2Avi Harlev3Iris Eisenberg4Tal Imbar5Rina Meidan6Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, IsraelDepartment of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, IsraelFertility and IVF Unit, Barzilai University Medical Center, Ashkelon 7830604, IsraelFertility and IVF Unit, Barzilai University Medical Center, Ashkelon 7830604, IsraelThe Magda and Richard Hoffman Center for Human Placenta Research, Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem 91240, IsraelThe Magda and Richard Hoffman Center for Human Placenta Research, Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem 91240, IsraelDepartment of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 7610001, IsraelGranulosa-lutein cells (GLCs) from PCOS women display reduced <i>HIF-1α</i> and <i>EDN2</i> levels, suggesting their role in PCOS etiology. Here, we investigated the mechanisms involved in aberrant <i>EDN2</i> expression in PCOS, and its association with <i>HIF-1α</i>. Various <i>HIF-1α</i>-dependent factors were studied in GLCs from PCOS and compared to normally ovulating women. MicroRNA-210 (miR-210), its target genes (<i>SDHD</i> and <i>GPD1L</i>), and <i>HIF-1α</i>-responsive genes (<i>EDN2</i> and <i>VEGFA</i>) differed in GLCs from PCOS, compared with those of healthy women. Levels of miR-210—designated hypoxiamiR—and <i>EDN2</i> were reduced in the PCOS GLCs; concomitantly, <i>GPD1L</i> and <i>SDHD</i> levels were elevated. Cultured GLCs retained low <i>EDN2</i> expression and had low <i>HIF-1α</i> levels, providing evidence for a disrupted hypoxic response in the PCOS GLCs. However, <i>VEGFA</i> expression was elevated in these cells. Next, miR-210 levels were manipulated. miR-210-mimic stimulated <i>EDN2</i> twice as much as the miR-NC-transfected cells, whereas miR-210-inhibitor diminished <i>EDN2,</i> emphasizing the importance of hypoxiamiR for <i>EDN2</i> induction. Intriguingly, <i>VEGFA</i> transcripts were reduced by both miR-210-mimic and -inhibitor, demonstrating that <i>EDN2</i> and <i>VEGFA</i> 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.https://www.mdpi.com/1422-0067/22/15/8216miR-210<i>VEGFA</i><i>HIF-1α</i>ovulationcorpus luteum |
| spellingShingle | Magdalena Szymanska Ketan Shrestha Eliezer Girsh Avi Harlev Iris Eisenberg Tal Imbar Rina Meidan Reduced Endothelin-2 and Hypoxic Signaling Pathways in Granulosa-Lutein Cells of PCOS Women International Journal of Molecular Sciences miR-210 <i>VEGFA</i> <i>HIF-1α</i> ovulation corpus luteum |
| title | Reduced Endothelin-2 and Hypoxic Signaling Pathways in Granulosa-Lutein Cells of PCOS Women |
| title_full | Reduced Endothelin-2 and Hypoxic Signaling Pathways in Granulosa-Lutein Cells of PCOS Women |
| title_fullStr | Reduced Endothelin-2 and Hypoxic Signaling Pathways in Granulosa-Lutein Cells of PCOS Women |
| title_full_unstemmed | Reduced Endothelin-2 and Hypoxic Signaling Pathways in Granulosa-Lutein Cells of PCOS Women |
| title_short | Reduced Endothelin-2 and Hypoxic Signaling Pathways in Granulosa-Lutein Cells of PCOS Women |
| title_sort | reduced endothelin 2 and hypoxic signaling pathways in granulosa lutein cells of pcos women |
| topic | miR-210 <i>VEGFA</i> <i>HIF-1α</i> ovulation corpus luteum |
| url | https://www.mdpi.com/1422-0067/22/15/8216 |
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