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>...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-07-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/15/8216 |
| Summary: | 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. |
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| ISSN: | 1661-6596 1422-0067 |