Altered endothelin expression in granulosa-lutein cells of women with polycystic ovary syndrome

Imbar, Tal; Klipper, Eyal; Greenfield, Caryn; Hurwitz, Arye; Haimov‐Kochman, Ronit; Meidan, Rina

doi:10.1016/j.lfs.2012.06.006

Cited by 15 publications

(13 citation statements)

References 55 publications

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“…Recently, we have reported that significantly lower levels of EDN2 were present in GCs derived from women with PCOS, compared with normally ovulating women (Imbar et al 2012). Their response in culture to luteotropic agents was also different from that in the control group (Imbar et al 2012), further demonstrating the importance of LH/hCG in EDN2 induction. The involvement of hypoxic conditions in the abnormal responses of GCs derived from women with PCOS is yet to be investigated.…”

Section: Discussionmentioning

confidence: 90%

“…It is characterized by anovulation, oligomenorrhea or amenorrhea, hyperandrogenism, and obesity and is related to insulin (Legro et al 2004). Recently, we have reported that significantly lower levels of EDN2 were present in GCs derived from women with PCOS, compared with normally ovulating women (Imbar et al 2012). Their response in culture to luteotropic agents was also different from that in the control group (Imbar et al 2012), further demonstrating the importance of LH/hCG in EDN2 induction.…”

Section: Discussionmentioning

confidence: 93%

“…EDN2 in follicles or CL was localized mainly to the luteal steroidogenic cells or luteinized human granulosa cells (GCs; Ko et al 2006, Klipper et al 2010, Imbar et al 2012. GCs collected from patients with polycystic ovary syndrome (PCOS), characterized among other symptoms, by chronic oligo-ovulation or anovulation, had significantly lower EDN2 mRNA expression when compared with normally ovulating women (Imbar et al 2012). Thus, this study helps in further establishing the roles of EDN2 in follicular rupture, ovulation, and CL formation.…”

Section: Introductionmentioning

confidence: 86%

“…Consistent with the contention that EDN2 is essential for CL formation, we reported that EDN2 mRNA levels were transiently expressed immediately after ovulation, in the early, developing bovine CL. EDN2 in follicles or CL was localized mainly to the luteal steroidogenic cells or luteinized human granulosa cells (GCs; Ko et al 2006, Klipper et al 2010, Imbar et al 2012. GCs collected from patients with polycystic ovary syndrome (PCOS), characterized among other symptoms, by chronic oligo-ovulation or anovulation, had significantly lower EDN2 mRNA expression when compared with normally ovulating women (Imbar et al 2012).…”

Section: Introductionmentioning

confidence: 99%

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HIF1A-dependent increase in endothelin 2 levels in granulosa cells: role of hypoxia, LH/cAMP, and reactive oxygen species

Yalu¹,

Oyesiji²,

Eisenberg³

et al. 2015

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Hypoxia-inducible factor 1 alpha (HIF1A) and endothelin 2 (EDN2) are transiently expressed during the same time window in the developing corpus luteum (CL). In this study, we sought to investigate the involvement of LH/cAMP, reactive oxygen species (ROS), and a hypoxia-mimetic compound (CoCl 2 ) on HIF1A expression and how it affected EDN2 levels, using transformed human granulosa cells (thGCs) and primary bovine granulosa cells (GCs). CoCl 2 elevated HIF1A protein levels in thGCs in a dose-dependent manner. Forskolin alone had no significant effect; however, forskolin and CoCl 2 together further induced HIF1A protein and EDN2 mRNA expression in thGCs. Similarly, in primary GCs, LH with CoCl 2 synergistically augmented HIF1A protein levels, which resulted in higher expression of EDN2 and another well-known hypoxia-inducible gene, VEGF (VEGFA). Importantly, LH alone elevated HIF1A mRNA but not its protein. The successful knockdown of HIF1A in thGCs using siRNA abolished hypoxia-induced EDN2 and also the additive effect of forskolin and CoCl 2 . We then examined the roles of ROS in thGCs: hydrogen peroxide (20 and 50 mM) elevated HIF1A protein as well as the expression of EDN2, implying that induction of HIF1A protein levels is sufficient to stimulate the expression of EDN2 (and VEGF) in normoxia. A broad-range ROS scavenger, butylated hydroxyanisole, inhibited CoCl 2 -induced HIF1A protein with a concomitant reduction in the mRNA expression of EDN2 and VEGF in thGCs. The results obtained in this study suggest that HIF1A, induced by various stimuli, is an essential mediator of EDN2 mRNA expression. The results may also explain the rise in the levels of HIF1A-dependent genes (EDN2 and VEGF) in the developing CL.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

HIF1A-dependent increase in endothelin 2 levels in granulosa cells: role of hypoxia, LH/cAMP, and reactive oxygen species

Yalu¹,

Oyesiji²,

Eisenberg³

et al. 2015

Reproduction

Self Cite

View full text Add to dashboard Cite

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“…This finding is consistent with our results in this study. Many studies have proven that EDN1 is highly expressed and demonstrates very important functions in the ovary and granulosa cells . FSH, hCG, IGF1, and GnRH regulate EDN1 expression in the ovary .…”

Section: Discussionmentioning

confidence: 99%

Effects of melatonin on the synthesis of estradiol and gene expression in pig granulosa cells

Liu

Yang

et al. 2019

Journal of Pineal Research

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The interaction of granulosa cells (GCs) with oocytes is important to regulate follicle development. The exogenous melatonin promoting the maturation of oocytes by GCs has been approved in pig, however, the transcriptome profile and the functions of the genes regulated by melatonin in GCs have not yet to be fully characterized. In this study, we found melatonin could stimulate the synthesis of estradiol in pig GCs. The RNA‐seq was used to explore the effects of melatonin on gene expression, a total of 89 differentially expressed genes (DEGs) were identified. Gene ontology analysis showed DEGs which associated with regulation of cell proliferation, cell cycle, and anti‐apoptosis were significantly enriched. The functions of two DEGs, NOTCH2 and FILIP1L, were studied in pig GCs. The results showed that NOTCH2 inhibited the synthesis of estradiol, but FILIP1L promoted the synthesis of estradiol. Furthermore, inhibiting NOTCH2 in granulosa cells cocultured with cumulus‐oocyte‐complexes had no obvious effect on the maturation of pig oocyte, but could upregulate the cleavage rate of oocyte. We proved that FILIP1L had no effect on the maturation and cleavage of pig oocytes. Our work deepens the understanding of melatonin's effects on GCs and oocyte. The DEGs we found will be beneficial to reveal mechanisms of melatonin acting on GCs and oocytes and design the pharmacological interventions.

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Expression and clinical significance of the HIF-1a/ET-2 signaling pathway during the development and treatment of polycystic ovary syndrome

et al. 2015

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Polycystic ovary syndrome (PCOS) is a major health problem in reproductive-aged women worldwide, but the precise pathogenesis of PCOS remains unclear. Our previous study revealed that hypoxia-inducible factor (HIF)-1a mediated endothelin (ET)-2 signaling plays an important role in ovulation in rats. Therefore, the present study used a PCOS rat model to test the hypotheses that HIF-1a signaling is expressed and inhibited in ovaries during PCOS formation and that the HIF-1a/ET-2 signaling pathway is a target of dimethyldiguanide (DMBG) in the clinical treatment of PCOS. First, the development of a PCOS model and the effect of DMBG treatment were examined through ovarian histology and serum hormone levels, which were consistent with previous reports. Second, HIF-1a and ET-2 expression were detected by immunohistochemistry and western blot. The results showed decreased HIF-1a/ET-2 expression in the ovaries of PCOS rats, whereas DMBG treatment reversed the protein decreases and improved the PCOS symptoms. Third, to understand the molecular mechanism, HIF-1a/ET-2 mRNA expression was also examined. Interestingly, HIF-1a mRNA increased in the ovaries of PCOS rats, while ET-2 mRNA decreased, indicating that HIF-1a protein degradation may be involved in POCS development and treatment. Finally, HIF prolyl hydroxylase (PHD) activity was examined to further clarify the contribution of HIF-1a signaling to the development and treatment of PCOS. The results suggested that the inhibition of HIF-1a/ET-2 signaling may be caused by increased PHD activity in PCOS. DMBG-treated PCOS may further activate HIF-1a signaling at least partly through inhibiting PHD activity. Taken together, these results indicate that HIF-1a signaling is inhibited in a PCOS rat model through increasing PHD activity. DMBG treatment improved PCOS by rescuing this pathway, suggesting that HIF-1a signaling plays an important role in the development and treatment of PCOS. This HIF-1a-mediated ET-2 signaling pathway may be an important mechanism regulating PCOS formation and treatment in mammalian ovaries in vivo and should be a new clinical target for PCOS prevention and treatment in the future.

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Altered endothelin expression in granulosa-lutein cells of women with polycystic ovary syndrome

Abstract: Dysregulation of ovarian endothelin expression may induce a pathologic ovulation pattern characteristic of PCOS.

Cited by 15 publications

References 55 publications

HIF1A-dependent increase in endothelin 2 levels in granulosa cells: role of hypoxia, LH/cAMP, and reactive oxygen species

HIF1A-dependent increase in endothelin 2 levels in granulosa cells: role of hypoxia, LH/cAMP, and reactive oxygen species

Effects of melatonin on the synthesis of estradiol and gene expression in pig granulosa cells

Expression and clinical significance of the HIF-1a/ET-2 signaling pathway during the development and treatment of polycystic ovary syndrome

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