scholarly journals Human BMP8A suppresses luteinization of rat granulosa cells via the SMAD1/5/8 pathway

Reproduction ◽  
2020 ◽  
Vol 159 (3) ◽  
pp. 315-324 ◽  
Author(s):  
Fang-Ju Wu ◽  
Ying-Wen Wang ◽  
Ching-Wei Luo
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Granulosa Cells ◽  
Polycystic Ovarian Syndrome ◽  
Ovarian Function ◽  
Cell Function ◽  
Type I ◽  
Type Ii ◽  
Related Gene ◽  
Inhibitory Effects ◽  
Ovarian Syndrome

Bone morphogenetic proteins (BMPs) are known to play an indispensable role in preventing the precocious luteinization of granulosa cells within growing ovarian follicles. In this study, we found that the transcripts of BMP8 genes are enriched in the ovaries of humans and rodents. When analyzing transcriptomic datasets obtained from human mature granulosa cells, we further found that the BMP8 transcripts not only show the highest abundance among the searchable BMP-related ligands but also decrease significantly in women of advanced age or women with polycystic ovarian syndrome. The correlation between the BMP8 levels in granulosa cells and the decline in ovarian function in these subjects suggests that BMP8 protein may be involved in the regulation of granulosa cell function(s). Using a rat model, we demonstrated that human BMP8A protein activates the SMAD1/5/8 and the SMAD2/3 pathways simultaneously in both immature and mature granulosa cells. Furthermore, the expression of potential type I and type II receptors used by BMP8 in rat granulosa cells was characterized. We found that BMP8A treatment can significantly inhibit gonadotropin-induced progesterone production and steroidogenesis-related gene expression in granulosa cells. Pathway dissection using receptor inhibitors further revealed that such inhibitory effects occur specifically through the BMP8-activated SMAD1/5/8, but not SMAD2/3, pathway. Taken together, considering its abundance and possible functions in granulosa cells, we suggest that BMP8 may act as a novel luteinization inhibitor in growing follicles.

scholarly journals Non-canonical progesterone signaling in granulosa cell function

Reproduction ◽  
2014 ◽  
Vol 147 (5) ◽  
pp. R169-R178 ◽  
Author(s):  
John J Peluso ◽  
James K Pru
Keyword(s):  
Granulosa Cell ◽  
Granulosa Cells ◽  
Polycystic Ovarian Syndrome ◽  
Cell Function ◽  
Reproductive Capacity ◽  
Dependent Manner ◽  
Follicle Growth ◽  
Altered Expression ◽  
Ovarian Syndrome ◽  
Enhancer Factor

It has been known for over 3 decades that progesterone (P4) suppresses follicle growth. It has been assumed that P4 acts directly on granulosa cells of developing follicles to slow their development, as P4 inhibits both mitosis and apoptosis of cultured granulosa cells. However, granulosa cells of developing follicles of mice, rats, monkeys, and humans do not express the A or B isoform of the classic nuclear receptor for P4 (PGR). By contrast, these granulosa cells express other P4 binding proteins, one of which is referred to as PGR membrane component 1 (PGRMC1). PGRMC1 specifically binds P4 with high affinity and mediates P4's anti-mitotic and anti-apoptotic action as evidenced by the lack of these P4-dependent effects in PGRMC1-depleted cells. In addition, mice in which PGRMC1 is conditionally depleted in granulosa cells show diminished follicle development. While the mechanism through which P4 activation of PGRMC1 affects granulosa cell function is not well defined, it appears that PGRMC1 controls granulosa cell function in part by regulating gene expression in T-cell-specific transcription factor/lymphoid enhancer factor-dependent manner. Clinically, altered PGRMC1 expression has been correlated with premature ovarian failure/insufficiency, polycystic ovarian syndrome, and infertility. These collective studies provide strong evidence that PGRMC1 functions as a receptor for P4 in granulosa cells and that altered expression results in compromised reproductive capacity. Ongoing studies seek to define the components of the signal transduction cascade through which P4 activation of PGRMC1 results in the regulation of granulosa cell function.

267. A role for transforming growth factor-β 1 (TGF-β1) during the establishment of folliculogenesis

2008 ◽  
Vol 20 (9) ◽  
pp. 67
Author(s):  
I. Kuyznierewicz ◽  
J. K. Findlay ◽  
A. E. Drummond
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Granulosa Cells ◽  
Transforming Growth Factor ◽  
Ovarian Function ◽  
Cell Function ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Cyclin D2 ◽  
Tgf Β1

A group of structurally related proteins, known as the transforming growth factor-β (TGF- β) superfamily, have been implicated in the local regulation of ovarian function. It is unclear what role TGF-β1–3 plays in folliculogenesis during the period after birth in the rat. We investigated whether the TGF-β ligands and their receptors were present during this period of development and the effects of TGF-β1 on granulosa cell function (proliferation, apoptosis, steroidogenesis). Ovaries from rats 4, 8 and 12 days of age were isolated and RNA extracted and reverse transcribed for real-time PCR. The expression of the TGF-β ligands and TGFβRI and TGFβRII were measured. Granulosa cells isolated from DES treated immature rats were treated with FSH (100ng/mL) and TGF-β1 (1 or 10ng/mL) for 2hr, n = 4 replicates. The RNA was extracted and prepared for RT–PCR. The expression of cyclin D2, FKHR, SCC, 3βHSD and StAR were measured. TGFβRI and TGFβRII proteins were localised to postnatal rat ovary by immunohistochemistry. TGF-β1–3, TGFβRI and TGFβRII were present in rat ovaries as early as 4 days after birth. Expression of TGF-β1 mRNA increased 2-fold between day 4 and 12. TGF-β2 and TGF-β3 mRNAs declined between day 4 and 8 and remained low at day 12. The type I and II TGF-β receptors were differentially regulated with TGFβRI expression high at day 4, declining at day 8. In contrast, TGFβRII appeared to be ubiquitously expressed. Cyclin D2 mRNA expression was enhanced in the presence of both TGF-β1 and FSH, whereas FKHR mRNA expression declined. TGF-β1 had no impact on the steroidogenic mRNAs. TGFβRI and TGFβRII proteins were localised to the cytoplasm of oocytes, granulosa cells and theca cells. These studies indicate that TGF-β1 can exert effects on ovarian folliculogenesis as it is established during the postnatal period. Proliferation and apoptosis appear to be targets of TGF-β1 action. Supported by the NHMRC of Australia (Regkeys 241000, 198705, 441101 & 465415)

scholarly journals Endothelin (ET)-1 and ET-3 inhibit estrogen and cAMP production by rat granulosa cells in vitro

1998 ◽  
Vol 157 (2) ◽  
pp. 209-215 ◽  
Author(s):  
AE Calogero ◽  
N Burrello ◽  
AM Ossino
Keyword(s):  
Granulosa Cells ◽  
Ovarian Function ◽  
Biological Effects ◽  
Female Rats ◽  
Dependent Manner ◽  
Camp Production ◽  
Inhibitory Effects ◽  
Ovarian Steroidogenesis ◽  
Estrogen Production ◽  
Etb Receptor

Endothelin (ET)-1 and ET-3, two peptides with a potent vasoconstrictive property, produce a variety of biological effects in different tissues by acting through two different receptors, the ET-1 selective ET(A) receptor and the non-selective ETB receptor. An increasing body of literature suggests that ET-1 acts as a paracrine/autocrine regulator of ovarian function. Indeed, ETB receptors have been identified in rat granulosa cells and ET-1 is a potent inhibitor of progesterone production. In contrast, inconsistent data have been reported about the role of ET-1 on estrogen production and the effects of ET-3 are not known. Therefore, the present study was undertaken to evaluate the effects of ET-1 and ET-3 on estrogen and cAMP production, and the receptor type involved. Given that prostanoids modulate ovarian steroidogenesis and that many actions of ETs are mediated by these compounds, we also evaluated whether the effects of ETs on estrogen and cAMP production might be prostanoid-mediated. ET-1, ET-3, and safarotoxin-S6c (SFX-S6c), a selective ETB receptor agonist, inhibited basal estrogen production by granulosa cells obtained from immature, estrogen-primed female rats, in a concentration-dependent manner. All three peptides were also capable of inhibiting the production of estrogen stimulated by a half-maximal (1 mIU/ml) and a maximally stimulatory (3 mIU/ml) concentration of FSH, ET-1 and ET-3 dose-dependently suppressed basal and FSH (1 mIU/ml)-stimulated cAMP production. ET-3 and SFX-S6c were significantly more potent than ET-1 in suppressing estrogen production, suggesting that this effect was not mediated by the ET(A) receptor. Indeed, BQ-123, a selective ET(A) receptor antagonist, did not influence the inhibitory effects of ET-1 and ET-3 on basal and FSH-stimulated estrogen release. To determine a possible involvement of prostanoids, we evaluated the effects of maximally effective concentrations of ET-1 and ET-3 on estrogen and cAMP production in the presence of indomethacin, a prostanoid synthesis inhibitor. This compound did not have any effect on the suppressive effects of ETs on basal or FSH (1 mIU/ml)-stimulated estrogen or cAMP production. In conclusion, ET-1 and ET-3 were able to inhibit estrogen and cAMP production by rat granulosa cells, indicating that the inhibitory effects of ETs on ovarian steroidogenesis are not limited to progesterone biosynthesis. This effect does not appear to be mediated by prostanoids or by the classical ET(A) and ETB receptors, at least under these experimental conditions.

scholarly journals miR‑132 is upregulated in polycystic ovarian syndrome and inhibits granulosa cells viability by targeting Foxa1

2020 ◽  
Vol 22 (6) ◽  
pp. 5155-5162
Author(s):  
Xiangrong Cui ◽  
Xuan Jing ◽  
Junfen Liu ◽  
Xingyu Bi ◽  
Xueqing Wu
Keyword(s):  
Granulosa Cells ◽  
Polycystic Ovarian Syndrome ◽  
Ovarian Syndrome

Fractalkine and apoptotic/anti-apoptotic markers in granulosa cells of women with polycystic ovarian syndrome

2020 ◽  
Vol 47 (5) ◽  
pp. 3593-3603
Author(s):  
Aydin Raei Sadigh ◽  
Masoud Darabi ◽  
Ali Salmassi ◽  
Kobra Hamdi ◽  
Laya Farzadi ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Polycystic Ovarian Syndrome ◽  
Apoptotic Markers ◽  
Ovarian Syndrome

Expression of inhibin α,βA and βB messenger ribonucleic acids in the normal human ovary and in polycystic ovarian syndrome

1994 ◽  
Vol 143 (1) ◽  
pp. 127-137 ◽  
Author(s):  
T-A Jaatinen ◽  
T-L Penttilä ◽  
A Kaipia ◽  
T Ekfors ◽  
M Parvinen ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Cellular Localization ◽  
Polycystic Ovarian Syndrome ◽  
Human Ovary ◽  
Α Subunit ◽  
Ribonucleic Acids ◽  
Theca Cells ◽  
Subunit Mrna ◽  
Normal Human ◽  
Ovarian Syndrome

Abstract We studied the cellular distribution of inhibin α, βA and βB mRNAs in the normal human ovary and in polycystic ovarian syndrome (PCOS) by in situ hybridization. Our results show that human granulosa cells express inhibin α, βA and βB subunit mRNAs, and theca cells express inhibin α and βA subunit mRNAs. The co-localization of α and βA mRNAs in theca cells supports the hypothesis that inhibin also has an autocrine function in these cells. We did not detect any inhibin subunit mRNA in the granulosa cells of atretic follicles, while theca cells also expressed α subunit mRNA in those follicles. The present findings suggest that the expression of inhibin subunits is regulated differently in human follicular granulosa and theca cells. It has been speculated that inhibin may be involved in the development of PCOS. Our results show that the cellular localization of inhibin subunit mRNAs is not disturbed in PCOS ovaries. Journal of Endocrinology (1994) 143, 127–137

scholarly journals Insulin and Insulin-Like Growth Factor Stimulation of Vascular Endothelial Growth Factor Production by Luteinized Granulosa Cells: Comparison between Polycystic Ovarian Syndrome (PCOS) and Non-PCOS Women

2007 ◽  
Vol 92 (7) ◽  
pp. 2726-2733 ◽  
Author(s):  
Meghan B. Stanek ◽  
Sherri M. Borman ◽  
Theodore A. Molskness ◽  
Janine M. Larson ◽  
Richard L. Stouffer ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Granulosa Cells ◽  
Polycystic Ovarian Syndrome ◽  
Culture Media ◽  
Vascular Endothelial ◽  
Vitro Fertilization ◽  
Endothelial Growth Factor ◽  
Ovarian Syndrome

Abstract Context: Vascular endothelial growth factor A (VEGF-A) is a potent cytokine that promotes angiogenesis and vascular permeability. After controlled ovarian stimulation (COS) for in vitro fertilization (IVF), excessive VEGF-A production can occur, particularly in women with polycystic ovarian syndrome (PCOS); however, it is unclear whether the regulation of VEGF-A production is different between PCOS and non-PCOS women. Objective: The aim of this study was to determine whether there were differences in the dose- and time-dependent effects of insulin and IGFs on VEGF-A production by luteinized granulosa cells (LGCs) from women with and without PCOS. Design and Setting: A prospective comparative experimental study was conducted at an institutional practice. Patients: Patients included six PCOS and six non-PCOS women undergoing COS and IVF. Interventions: Interventions included COS for IVF. Main Outcome Measures: VEGF-A levels in culture media were collected daily for 3 d from LGCs after incubation with variable doses of insulin, IGF-I, and IGF-II in the presence and absence of LH. Results: In both study groups, exposure to LH alone did not alter VEGF-A levels. However, insulin or IGF increased VEGF-A levels within 1 d and appeared to synergize with LH at 3 d. VEGF-A production by non-PCOS LGCs was more sensitive to IGF exposure, whereas PCOS cells were more sensitive to insulin. Although an increase in DNA content (P < 0.05) was noted in cultures of PCOS cells, progesterone levels were lower compared with non-PCOS LGCs. Conclusion: Insulin and IGFs promote VEGF-A production in LGCs, but the response patterns are different when cells from PCOS and non-PCOS women are compared.

scholarly journals Mutant Activin-Like Kinase 2 in Fibrodysplasia Ossificans Progressiva are Activated via T203 by BMP Type II Receptors

2015 ◽  
Vol 29 (1) ◽  
pp. 140-152 ◽  
Author(s):  
Mai Fujimoto ◽  
Satoshi Ohte ◽  
Kenji Osawa ◽  
Arei Miyamoto ◽  
Sho Tsukamoto ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Soft Tissues ◽  
Genetic Disorder ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Type Ii ◽  
Activin Receptor ◽  
Bmp Receptors

Abstract Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder characterized by progressive heterotopic ossification in soft tissues, such as the skeletal muscles. FOP has been shown to be caused by gain-of-function mutations in activin receptor-like kinase (ALK)-2, which is a type I receptor for bone morphogenetic proteins (BMPs). In the present study, we examined the molecular mechanisms that underlie the activation of intracellular signaling by mutant ALK2. Mutant ALK2 from FOP patients enhanced the activation of intracellular signaling by type II BMP receptors, such as BMPR-II and activin receptor, type II B, whereas that from heart disease patients did not. This enhancement was dependent on the kinase activity of the type II receptors. Substitution mutations at all nine serine and threonine residues in the ALK2 glycine- and serine-rich domain simultaneously inhibited this enhancement by the type II receptors. Of the nine serine and threonine residues in ALK2, T203 was found to be critical for the enhancement by type II receptors. The T203 residue was conserved in all of the BMP type I receptors, and these residues were essential for intracellular signal transduction in response to ligand stimulation. The phosphorylation levels of the mutant ALK2 related to FOP were higher than those of wild-type ALK2 and were further increased by the presence of type II receptors. The phosphorylation levels of ALK2 were greatly reduced in mutants carrying a mutation at T203, even in the presence of type II receptors. These findings suggest that the mutant ALK2 related to FOP is enhanced by BMP type II receptors via the T203-regulated phosphorylation of ALK2.

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