TY - JOUR
T1 - Reduced endothelin-2 and hypoxic signaling pathways in granulosa-lutein cells of PCOS women
AU - Szymanska, Magdalena
AU - Shrestha, Ketan
AU - Girsh, Eliezer
AU - Harlev, Avi
AU - Eisenberg, Iris
AU - Imbar, Tal
AU - Meidan, Rina
N1 - Funding Information:
This research was supported by the German–Israeli Foundation for Scientific Research and Development (GIF), grant number I-1417-201.2/2017, and by the Robert H. Smith Faculty of Agriculture, Food, and Environment Research Fund for International Cooperation scholarship. The cost of Open Access publication was covered by the Society for Biology of Reproduction in Poland.
Funding Information:
Acknowledgments: The authors are grateful to the German–Israeli Foundation for Scientific Re‐ search and Development for funding this work, and to the International School of Agricultural Sci‐ ences, The Robert H. Smith Faculty of Agriculture, Food, and Environment for providing a fellow‐ ship to M. Szymanska, and to the Society for Biology of Reproduction in Poland for covering the cost of Open Access publication fees.
Funding Information:
Funding: This research was supported by the German–Israeli Foundation for Scientific Research and Development (GIF), grant number I‐1417‐201.2/2017, and by the Robert H. Smith Faculty of Agriculture, Food, and Environment Research Fund for International Cooperation scholarship. The cost of Open Access publication was covered by the Society for Biology of Reproduction in Poland.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - Granulosa-lutein cells (GLCs) from PCOS women display reduced HIF-1α and EDN2 lev-els, suggesting their role in PCOS etiology. Here, we investigated the mechanisms involved in ab-errant EDN2 expression in PCOS, and its association with HIF-1α. Various HIF-1α-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-1α-responsive genes (EDN2 and VEGFA) differed in GLCs from PCOS, compared with those of healthy women. Levels of miR-210— designated hypoxiamiR—and EDN2 were reduced in the PCOS GLCs; concomitantly, GPD1L and SDHD levels were elevated. Cultured GLCs retained low EDN2 expression and had low HIF-1α 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.
AB - Granulosa-lutein cells (GLCs) from PCOS women display reduced HIF-1α and EDN2 lev-els, suggesting their role in PCOS etiology. Here, we investigated the mechanisms involved in ab-errant EDN2 expression in PCOS, and its association with HIF-1α. Various HIF-1α-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-1α-responsive genes (EDN2 and VEGFA) differed in GLCs from PCOS, compared with those of healthy women. Levels of miR-210— designated hypoxiamiR—and EDN2 were reduced in the PCOS GLCs; concomitantly, GPD1L and SDHD levels were elevated. Cultured GLCs retained low EDN2 expression and had low HIF-1α 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.
KW - Corpus luteum
KW - HIF-1α
KW - MiR-210
KW - Ovulation
KW - VEGFA
UR - http://www.scopus.com/inward/record.url?scp=85111392439&partnerID=8YFLogxK
U2 - 10.3390/ijms22158216
DO - 10.3390/ijms22158216
M3 - Article
C2 - 34360981
AN - SCOPUS:85111392439
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 15
M1 - 8216
ER -