EET Reduction Contributes to Granulosa Cell Senescence And Endometriosis-Associated Infertility Via the PI3K/AKT/mTOR Signaling Pathway
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PROVIDER: PRJNA1301370 | ENA |
REPOSITORIES: ENA
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Project description:Oxidative stress is involved in endometriosis (EM)-related infertility via various mechanisms, such as accelerating ovarian granulosa cell (GC) senescence, inhibiting ovulation, and interfering with lipid metabolism. In this study, we aimed to examine abnormal oxidative lipid levels and their related mechanisms in EM-associated infertility. Through liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis, we observed that epoxyeicosatrienoic acids (EETs), which have antioxidant and anti-senescence effects, had decreased levels in follicular fluid samples from EM patients. The EET levels were positively correlated with in vitro fertilization outcomes. Using qPCR and western blot experiments, we found elevated soluble epoxide hydrolase (EPHX2) expression levels in EM-GCs. This enzyme metabolizes EETs into dihydroxyeicosatrienoic acids (DHETs), explaining the decreased 14, 15-EET levels in EM patients. Lower 14, 15-EET concentrations led to decreased GC antioxidant capacity, reduced ATP production, reactive oxygen species (ROS) accumulation in oocytes, and abnormal cumulus-oocyte complex (COC) expansion, which ultimately resulted in decreased fertility. Inhibiting EPHX2 in vivo or in vitro could reverse these observed abnormalities by upregulating 14, 15-EET. Mechanistic studies showed that 14, 15-EET alleviated GC senescence and improved fertility by inhibiting excessive PI3K/AKT/mTOR signaling pathway activation in EM-GCs. Moreover, the PI3K/AKT/mTOR pathway inhibitor BEZ-235 significantly alleviated ROS-induced cell senescence and abnormal COC expansion. Further work showed that an oxidative stress-induced decrease in EZH2/H3K27Me3 histone methylation led to the elevated EPHX2 expression patterns in EM-GCs. In addition, the decreased 14, 15-EET levels led to ROS accumulation, decreased EZH2 enzymatic activity, less EPHX2/H3K27Me3 histone methylation, and increased EPHX2 protein expression levels, which further reduced 14, 15-EET levels as part of a vicious feedback loop. Using LC-MS/MS, viral infection, transcriptomic sequencing, knockout mice, and EM mouse model experiments, we elucidated the molecular mechanisms of 14, 15-EET in EM-associated infertility and the mechanism controlling its decreased levels.
2025-08-05 | GSE304488 | GEO
Project description:The mechanism by which endometriosis, a common gynecological disease characterized by chronic pelvic pain and infertility, causes infertility remains elusive. Luteinized unruptured follicle syndrome, the most common type of ovulatory dysfunction, is a cause of endometriosis-associated infertility involving reduced numbers of retrieved and mature oocytes. Ovulation is controlled by luteinizing hormone and paracrine signals produced within the follicle microenvironment. Generally, interleukin (IL)-1β is elevated in endometriosis follicular fluid, whereby it amplifies ovulation signals by activating extracellular-regulated kinase 1/2 and CCAAT/enhancer binding protein β pathways. However, this amplification of ovulation by IL-1β does not occur in patients with endometriosis. To illuminate the mechanism of ovulatory dysfunction in endometriosis, we analyzed the impact of oxidative stress and IL-1β expression in endometriosis follicles. We found that oxidative stress decreased EZH2 expression and reduced H3K27Me3 levels in endometriosis ovarian granulosa cells (GCs). Selective Ezh2 depletion in mice ovarian GCs reduced fertility by disturbing cumulus-oocyte complex expansion and reducing epidermal growth factor-like factor expression. Gene expression and H3K27Me3 ChIP-sequencing of GCs revealed IL-1 receptor 2 (IL-1R2), a high-affinity IL-1β-receptor that suppresses IL-1β-mediated inflammatory cascades during ovulation, as a crucial target gene of the EZH2-H3K27Me3 axis. Moreover, IL-1β addition did not restore ovulation upon Ezh2 knockdown, indicating a vital function of IL-1R2 in endometriosis. Thus, our findings show that reducing EZH2 and H3K27Me3 in GCs suppressed ovulatory signals by increasing IL-1R2 expression, which may ultimately contribute to endometriosis-associated infertility.
2025-02-28 | GSE218976 | GEO
Project description:The mechanism by which endometriosis, a common gynecological disease characterized by chronic pelvic pain and infertility, causes infertility remains elusive. Luteinized unruptured follicle syndrome, the most common type of ovulatory dysfunction, is a cause of endometriosis-associated infertility involving reduced numbers of retrieved and mature oocytes. Ovulation is controlled by luteinizing hormone and paracrine signals produced within the follicle microenvironment. Generally, interleukin (IL)-1β is elevated in endometriosis follicular fluid, whereby it amplifies ovulation signals by activating extracellular-regulated kinase 1/2 and CCAAT/enhancer binding protein β pathways. However, this amplification of ovulation by IL-1β does not occur in patients with endometriosis. To illuminate the mechanism of ovulatory dysfunction in endometriosis, we analyzed the impact of oxidative stress and IL-1β expression in endometriosis follicles. We found that oxidative stress decreased EZH2 expression and reduced H3K27Me3 levels in endometriosis ovarian granulosa cells (GCs). Selective Ezh2 depletion in mice ovarian GCs reduced fertility by disturbing cumulus-oocyte complex expansion and reducing epidermal growth factor-like factor expression. Gene expression and H3K27Me3 ChIP-sequencing of GCs revealed IL-1 receptor 2 (IL-1R2), a high-affinity IL-1β-receptor that suppresses IL-1β-mediated inflammatory cascades during ovulation, as a crucial target gene of the EZH2-H3K27Me3 axis. Moreover, IL-1β addition did not restore ovulation upon Ezh2 knockdown, indicating a vital function of IL-1R2 in endometriosis. Thus, our findings show that reducing EZH2 and H3K27Me3 in GCs suppressed ovulatory signals by increasing IL-1R2 expression, which may ultimately contribute to endometriosis-associated infertility.
2025-02-28 | GSE218980 | GEO
Project description:MIG-6 loss caused progesterone resistance through ERBB2 overexpression in non-receptive endometrium of endometriosis-related infertility. We used microarrays to understand the molecular mechanisms of progesterone resistance in infertility
2019-11-30 | GSE138185 | GEO
Project description:Analysis of lncRNA expression in endometriosis infertility, tubal disease infertility and normal subjects
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Project description:RNA sequencing was conducted for RNA expression profiling from GCs of five women with ovarian endometriosis and five with tubal factor infertility. The differential expression of mRNAs, lncRNAs, and circRNAs was compared. Then, the lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA networks were constructed by co-expressing lncRNA/circRNA and mRNAs.
2024-12-25 | GSE192636 | GEO
Project description:We found differential expression of lncRNA in the endometrium of patients with endometriosis compared to controls.
2024-03-23 | GSE262037 | GEO
Project description:Endometriosis is a common disease seen by gynecologists. Clinical features involve pelvic pain and unexplained infertility. Although endometriosis is pathologically characterized by endometrial tissue outside the normal uterine location, endometriosis is otherwise not easily explained. Endometriomas, endometriotic cysts of the ovary, typically cause pain and distortion of pelvic anatomy. To begin to understand the pathogenesis of endometriomas, we carried out transcriptome:microRNAome analysis of endometriomas and eutopic endometrium, using gene expression arrays and next generation small RNA sequencing technology. Keywords: two group comparison Patients undergoing surgery for endometriomas, suspected endometriosis, pelvic pain, abnormal uterine bleeding, pelvic organ prolapse, or uterine leiomyomas were approached for participation. After informed consent, the patients underwent scheduled surgical procedure. Tissues were collected either as cyst wall of endometrioma or endometrial curettage of hysterectomy specimen and placed directly into RNALater (Ambion, Austin, TX) and eventually frozen at -80?C. Samples were designated as endometriomas or non-endometriosis control endometrium based on surgical pathology reports. Total RNA was isolated from frozen tissue. High quality RNA was subjected to Illumina’s Human WG-6 version 2.0 BeadChips (Illumina). . *** This Series represents the transcriptome component of the study. ***
2011-05-09 | E-GEOD-23339 | biostudies-arrayexpress
Project description:To investigate the different function of endometriosis-related infertile patients follicular fluid (EMFF) and follicular fluid in control group (COFF), follicular fluid was collected and used for RNA sequencing.
2022-06-15 | GSE205494 | GEO
Project description:The Female Holobiont of Endometriosis and other Infertility-associated Conditions Raw sequence reads
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