Reduced Endothelin-2 and Hypoxic Signaling Pathways in Granulosa-Lutein Cells of PCOS Women

Granulosa-lutein cells (GLCs) from PCOS women display reduced and levels, suggesting their role in PCOS etiology. Here, we investigated the mechanisms involved in aberrant expression in PCOS, and its association with . Various -dependent factors were studied in GLCs from PCOS and compared to normally ovulating women. MicroRNA-210 (miR-210), its target genes ( and ), and -responsive genes ( and ) differed in GLCs from PCOS, compared with those of healthy women. Levels of miR-210-designated hypoxiamiR-and were reduced in the PCOS GLCs; concomitantly, and levels were elevated. Cultured GLCs retained low expression and had low levels, providing evidence for a disrupted hypoxic response in the PCOS GLCs. However, expression was elevated in these cells. Next, miR-210 levels were manipulated. miR-210-mimic stimulated twice as much as the miR-NC-transfected cells, whereas miR-210-inhibitor diminished emphasizing the importance of hypoxiamiR for induction. Intriguingly, transcripts were reduced by both miR-210-mimic and -inhibitor, demonstrating that and 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.