Notch Signaling Induced by Endoplasmic Reticulum Stress Regulates Cumulus-Oocyte Complex Expansion in Polycystic Ovary Syndrome

Koike, Hiroshi; Harada, Miyuki; Kusamoto, Akari; Kunitomi, Chisato; Xu, Zhi-Fang; Tanaka, Tsurugi; Urata, Yoko; Nose, Emi; Takahashi, Nozomi; Wada-Hiraike, Osamu; Hirota, Yasushi; Koga, Kaori; Osuga, Yutaka

doi:10.3390/biom12081037

Cited by 16 publications

(9 citation statements)

References 47 publications

(77 reference statements)

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“…70 The ovarian morphology of patients with PCOS is characterized as PCOM with interstitial fibrosis. 71 We demonstrated that ER stress contributes to the pathophysiology of PCOS through multiple functional alterations in granulosa cells 48,52,53,[72][73][74] (Figure 3). ER stress stimulates the production of transforming growth factor-β1 (TGF-β1), a profibrotic growth factor, in granulosa cells and accelerates interstitial fibrosis in the ovary, which is a characteristic of PCOS.…”

Section: Er Stress In Pcosmentioning

confidence: 94%

“… 76 Measurement of the diameters of COCs showed that the ER stress‐Notch pathway increases the size of COCs, although it remains to be determined whether such hypermaturity of COCs plays a causative role in the ovulatory dysfunction that characterizes PCOS. 74 …”

Section: Role Of Follicular Er Stress In the Patho...mentioning

confidence: 99%

“…Furthermore, ER stress induces the expression of multiple genes associated with cumulus oocyte‐complex (COC) expansion in granulosa cells via Notch signaling, one of the most evolutionarily highly conserved signaling systems, which regulates various cellular processes via juxtacrine cell–cell interactions 76 . Measurement of the diameters of COCs showed that the ER stress‐Notch pathway increases the size of COCs, although it remains to be determined whether such hypermaturity of COCs plays a causative role in the ovulatory dysfunction that characterizes PCOS 74 …”

Section: Role Of Follicular Er Stress In the Pathophysiology Of Pcosmentioning

confidence: 99%

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Pathophysiology of polycystic ovary syndrome revisited: Current understanding and perspectives regarding future research

Harada

2022

Reprod Medicine & Biology

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Background Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive‐age women and has lifelong effects on health. Methods In this review, I discuss the pathophysiology of PCOS. First, I summarize our current understanding of the etiology and pathology of PCOS, then, discuss details of two representative environmental factors involved in the pathogenesis of PCOS. Finally, I present perspectives regarding the directions of future research. Main findings The pathophysiology of PCOS is heterogeneous and shaped by the interaction of reproductive dysfunction and metabolic disorders. Hyperandrogenism and insulin resistance exacerbate one another during the development of PCOS, which is also affected by dysfunction of the hypothalamus‐pituitary‐ovarian axis. PCOS is a highly heritable disorder, and exposure to certain environmental factors causes individuals with predisposing genetic factors to develop PCOS. The environmental factors that drive the development of PCOS pathophysiology make a larger contribution than the genetic factors, and may include the intrauterine environment during the prenatal period, the follicular microenvironment, and lifestyle after birth. Conclusion On the basis of this current understanding, three areas are proposed to be subjects for future research, with the ultimate goals of developing therapeutic and preventive strategies and providing appropriate lifelong management, including preconception care.

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Section: Er Stress In Pcosmentioning

confidence: 94%

Section: Role Of Follicular Er Stress In the Patho...mentioning

confidence: 99%

Section: Role Of Follicular Er Stress In the Pathophysiology Of Pcosmentioning

confidence: 99%

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Pathophysiology of polycystic ovary syndrome revisited: Current understanding and perspectives regarding future research

Harada

2022

Reprod Medicine & Biology

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“…Notch signaling in the follicular microenvironment also regulates ovarian development, including follicular assembly and growth, steroidogenesis, and angiogenesis ( 34 , 96 , 97 ). Notch signaling is activated in the GCs of patients and mice with PCOS ( 98 ). The UPR activates Notch signaling followed by the induction of some ovulation-related genes in cultured human GCs.…”

Section: Pathophysiological Role Of Er Stress In Pcosmentioning

confidence: 99%

Roles of endoplasmic reticulum stress in the pathophysiology of polycystic ovary syndrome

Koike

Harada²,

Kusamoto³

et al. 2023

Front. Endocrinol.

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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women, affecting up to 15% of women in this group, and the most common cause of anovulatory infertility. Although its etiology remains unclear, recent research has revealed the critical role of endoplasmic reticulum (ER) stress in the pathophysiology of PCOS. ER stress is defined as a condition in which unfolded or misfolded proteins accumulate in the ER because of an imbalance in the demand for protein folding and the protein-folding capacity of the ER. ER stress results in the activation of several signal transduction cascades, collectively termed the unfolded protein response (UPR), which regulates various cellular activities. In principle, the UPR restores homeostasis and keeps the cell alive. However, if the ER stress cannot be resolved, it induces programmed cell death. ER stress has recently been recognized to play diverse roles in both physiological and pathological conditions of the ovary. In this review, we summarize current knowledge of the roles of ER stress in the pathogenesis of PCOS. ER stress pathways are activated in the ovaries of both a mouse model of PCOS and in humans, and local hyperandrogenism in the follicular microenvironment associated with PCOS is responsible for activating these. The activation of ER stress contributes to the pathophysiology of PCOS through multiple effects in granulosa cells. Finally, we discuss the potential for ER stress to serve as a novel therapeutic target for PCOS.

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“…A common and highly conserved signal transduction pathway that is activated via direct cell-to-cell contacts is the NOTCH signal pathway. It has already been shown in mammalian ovaries [4,5] that this pathway is important for the recruitment of primordial follicles [6,7] during folliculogenesis [8], as well as for oocyte development and the proliferation and function of granulosa cells [9][10][11][12]. The expression of the components of this signaling pathway is highly dynamic and, among others, depends on the oestrous cycle [13].…”

Section: Introductionmentioning

confidence: 99%

Translocation of Oocytic HES1 into Surrounding Cumulus Cells in Bovine: Mechanism of Cellular Interaction during IVM?

Pöhland

Vanselow

Sterza

2023

IJMS

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HES1 (hairy and enhancer of split-1, effector of the NOTCH pathway) plays a role in oocyte maturation and has been detected so far mainly in somatic follicular cells. In this study, we aimed to investigate whether HES1 is present in both compartments of bovine cumulus oocyte complexes (COCs) and whether in vitro maturation itself has an effect on its distribution. We investigated the abundance of HES1 mRNA and protein in bovine COCs characterized by Brilliant-Cresyl-Blue (BCB) stainability by RT-PCR and immunofluorescence before and after in vitro maturation (IVM). To study the interaction of the compartments and the possible translocation of HES1, we injected GFP-HES1 mRNA into oocytes before maturation and analyzed fluorescence recovery after photobleaching (FRAP). The results showed that HES1 mRNA was detectable in oocytes but not in cumulus cells. The number of transcripts increased with maturation, especially in BCB-positive oocytes. In contrast, the protein was mainly visible in cumulus cells both before and after maturation. After GFP-HES1-mRNA injection into oocytes, a signal could be detected not only in the oocytes but also in cumulus cells. Our result shows a nearly exclusive distribution of HES1 mRNA and protein in oocytes and cumulus cells, respectively, that might be explained by the transfer of the protein from the oocyte into cumulus cells.

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Notch Signaling Induced by Endoplasmic Reticulum Stress Regulates Cumulus-Oocyte Complex Expansion in Polycystic Ovary Syndrome

Cited by 16 publications

References 47 publications

Pathophysiology of polycystic ovary syndrome revisited: Current understanding and perspectives regarding future research

Pathophysiology of polycystic ovary syndrome revisited: Current understanding and perspectives regarding future research

Roles of endoplasmic reticulum stress in the pathophysiology of polycystic ovary syndrome

Translocation of Oocytic HES1 into Surrounding Cumulus Cells in Bovine: Mechanism of Cellular Interaction during IVM?

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