Imbalance between proliferation and apoptosis−related impaired GPR30 expression is involved in preeclampsia

Li, Jianxin; Chen, Zhu; Zhou, Xiaobo; Shi, Shuming; Qi, Hongbo; Baker, Philip N.; Zhang, Hua

doi:10.1007/s00441-016-2466-y

Cited by 22 publications

(14 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Apoptosis is an essential feature of normal placental development . However, it has been reported that apoptosis is implicated in the pathophysiology of PE . In our previous study, we found that the hypomethylation of fatty acid binding protein 4 induces trophoblastic cell apoptosis by regulation of inflammation and lipid metabolism disorder under hypoxia .…”

Section: Discussionmentioning

confidence: 72%

Hypermethylation of endoplasmic reticulum disulfide oxidase 1α leads to trophoblast cell apoptosis through endoplasmic reticulum stress in preeclampsia

Xiong

Ding

Gao

et al. 2018

J of Cellular Biochemistry

View full text Add to dashboard Cite

Abnormal trophoblast cell apoptosis is implicated in the pathogenesis of pregnancy-related disorders including preeclampsia (PE), and endoplasmic reticulum (ER) stress has been considered as a novel pathway in the regulation of cell apoptosis. In this study, we observed that both apoptosis and ER stress are triggered in trophoblast cells under hypoxia as well as in the placenta of PE rats. Quantitative polymerase chain reaction and Western blot analysis showed that the expression of endoplasmic reticulum disulfide oxidase 1α (ERO1α) is suppressed in trophoblast cells under hypoxia due to the hypermethylation of the ERO1α promoter region, and the inhibition of ERO1α expression plays an important role in ER stress and trophoblast cell apoptosis. Furthermore, we found that DNA methyltransferase 1 (DNMT1) is a key methyltransferase for DNA methylation in the regulation of ERO1α expression, and the binding level of DNMT1 to the ERO1α promoter is markedly elevated under hypoxia although DNMT1 expression is inhibited by hypoxia, suggesting that the binding level of DNMT1 to the ERO1α promoter region rather than the DNMT1 expression level contributes to the hypermethylation of ERO1α. Taken together, these results demonstrate that the hypermethylation of ERO1α mediated by increased binding of DNMT1 to the ERO1α promoter leads to trophoblast cell apoptosis through ER stress in the placenta of PE rats, which shed insight into the etiology of PE and might present a validated therapeutic target for the treatment of PE.

show abstract

Section: Discussionmentioning

confidence: 72%

Hypermethylation of endoplasmic reticulum disulfide oxidase 1α leads to trophoblast cell apoptosis through endoplasmic reticulum stress in preeclampsia

Xiong

Ding

Gao

et al. 2018

J of Cellular Biochemistry

View full text Add to dashboard Cite

show abstract

“…Alterations of the estrogen–estrogen receptors signaling have been associated with different pathologies of the reproductive system (e.g., preeclampsia, endometrial cancer, etc.). For example, low GPR30 expression levels, increased apoptosis, and reduced proliferation were associated with preeclampsia, and the pharmacological targeting of GPR30 might have clinical relevance [ 66 ]. Estrogen-induced PI3K–AKT signaling activated by GPR30 is involved in the regulation of endometrial cancer cell proliferation [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

Beta-Estradiol Regulates Voltage-Gated Calcium Channels and Estrogen Receptors in Telocytes from Human Myometrium

Banciu

Mustăciosu

et al. 2018

IJMS

View full text Add to dashboard Cite

Voltage-gated calcium channels and estrogen receptors are essential players in uterine physiology, and their association with different calcium signaling pathways contributes to healthy and pathological conditions of the uterine myometrium. Among the properties of the various cell subtypes present in human uterine myometrium, there is increasing evidence that calcium oscillations in telocytes (TCs) contribute to contractile activity and pregnancy. Our study aimed to evaluate the effects of beta-estradiol on voltage-gated calcium channels and estrogen receptors in TCs from human uterine myometrium and to understand their role in pregnancy. For this purpose, we employed patch-clamp recordings, ratiometric Fura-2-based calcium imaging analysis, and qRT-PCR techniques for the analysis of cultured human myometrial TCs derived from pregnant and non-pregnant uterine samples. In human myometrial TCs from both non-pregnant and pregnant uterus, we evidenced by qRT-PCR the presence of genes encoding for voltage-gated calcium channels (Cav3.1, Ca3.2, Cav3.3, Cav2.1), estrogen receptors (ESR1, ESR2, GPR30), and nuclear receptor coactivator 3 (NCOA3). Pregnancy significantly upregulated Cav3.1 and downregulated Cav3.2, Cav3.3, ESR1, ESR2, and NCOA3, compared to the non-pregnant condition. Beta-estradiol treatment (24 h, 10, 100, 1000 nM) downregulated Cav3.2, Cav3.3, Cav1.2, ESR1, ESR2, GRP30, and NCOA3 in TCs from human pregnant uterine myometrium. We also confirmed the functional expression of voltage-gated calcium channels by patch-clamp recordings and calcium imaging analysis of TCs from pregnant human myometrium by perfusing with BAY K8644, which induced calcium influx through these channels. Additionally, we demonstrated that beta-estradiol (1000 nM) antagonized the effect of BAY K8644 (2.5 or 5 µM) in the same preparations. In conclusion, we evidenced the presence of voltage-gated calcium channels and estrogen receptors in TCs from non-pregnant and pregnant human uterine myometrium and their gene expression regulation by beta-estradiol in pregnant conditions. Further exploration of the calcium signaling in TCs and its modulation by estrogen hormones will contribute to the understanding of labor and pregnancy mechanisms and to the development of effective strategies to reduce the risk of premature birth.

show abstract

“…G-protein-coupled receptor 30 (GPR30), identified as a novel estrogen receptor in 2005 has been suggested to mediate the action of estrogen (12,13). Recently, we also reported that GPR30 is involved in the development of preeclampsia (14,15). GPR30 is a specific receptor for 17β-estradiol, a form of estrogens (16), and is expressed in endothelial cells.…”

Section: Introductionmentioning

confidence: 92%

G-protein-coupled receptor 30 mediates the effects of estrogen on endothelial cell tube formation in vitro

Zhou

Chen

Mao

et al. 2017

International Journal of Molecular Medicine

Self Cite

View full text Add to dashboard Cite

The placenta is the exchange organ between the mother and the fetus. The inadequate function of this organ is associated with a number of pregnancy disorders. Hypoxia and oxidative stress during placental development may induce endothelial dysfunction, resulting in the reduction in the perfusion of the placenta. During pregnancy, the levels of estrogen are increased. Decreased estrogen levels have been reported in women with preeclampsia. However, whether estrogen is involved in placental angiogenesis remains unclear. In this study, we aimed to investigate the effects of estrogen on endothelial cell tube formation and to elucidate the underlying mechanisms. For this purpose, human umbilical vein endothelial cells (HUVECs) were cultured with 17-β-estradiol under conditions of hypoxia/reoxygenation (H/R). The total pipe length of the tube-like structure on endothelial cells was measured. The expression levels of G-protein-coupled receptor 30 (GPR30) and endothelial nitric oxide synthase (eNOS) and Akt were also measured in the endothelial cells following treatment with 17-β-estradiol under H/R conditions by western blot analysis and immunostaining. We found that the total pipe length of the tube-like structure on endothelial cells was significantly reduced. This reduction was reversed by treatment with 17-β-estradiol. The expression of GPR30 in endothelial cells was significantly increased following treatment with 17-β-estradiol under H/R conditions. Furthermore, the levels of eNOS and Akt in endothelial cells were also significantly increased following treatment with 17-β-estradiol under H/R conditions. The activation of eNOS was inhibited by wortmannin, an inhibitor of PI3K/Akt. Our data thus demonstrate that estrogen prevents the failure of endothelial cell tube formation induced by H/R. GPR30 plays an important role in these protective effects through the activation of eNOS and Akt in endothelial cells. Our data suggest that increased levels of estrogen are important for placental angiogenesis.

show abstract

Imbalance between proliferation and apoptosis−related impaired GPR30 expression is involved in preeclampsia

Abstract: Abstract:Introduction: Pre-eclampsia (PE) is associated with lowered circulating levels of oestrogen. The

Cited by 22 publications

References 70 publications

Hypermethylation of endoplasmic reticulum disulfide oxidase 1α leads to trophoblast cell apoptosis through endoplasmic reticulum stress in preeclampsia

Hypermethylation of endoplasmic reticulum disulfide oxidase 1α leads to trophoblast cell apoptosis through endoplasmic reticulum stress in preeclampsia

Beta-Estradiol Regulates Voltage-Gated Calcium Channels and Estrogen Receptors in Telocytes from Human Myometrium

G-protein-coupled receptor 30 mediates the effects of estrogen on endothelial cell tube formation in vitro

Contact Info

Product

Resources

About