In vivo effects of a GPR30 antagonist

Dennis, Megan K.; Burai, Ritwik; Ramesh, Chinnasamy; Petrie, Whitney K.; Alcon, Sara N; Nayak, Tapan K.; Bologa, Cristian; Leitão, Andrei; Brǎiloiu, Eugen; Deliu, Elena; Dun, Nae J.; Sklar, Larry A.; Hathaway, Helen J.; Arterburn, Jeffrey B.; Oprea, Tudor I.; Prossnitz, Eric R.

doi:10.1038/nchembio.168

Cited by 465 publications

(476 citation statements)

References 44 publications

(53 reference statements)

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“…EdU incorporation was assessed by the Click-iT EdU flow cytometry assay kit (Lifetech, Carlsbad, CA). To assess the impact of the GPER antagonist, G15 47 (Calbiochem-Novabiochem), on E2 or G1 effects on proliferation, cells were treated with G15 (µmol/L) for 15 minutes before addition of these agonists.…”

Section: Assessment Of Regulation Of Dna Synthesis As An Index Of Promentioning

confidence: 99%

Extent of Vascular Remodeling Is Dependent on the Balance Between Estrogen Receptor α and G-Protein–Coupled Estrogen Receptor

et al. 2016

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Abstract-Estrogens are important regulators of cardiovascular function. Some of estrogen's cardiovascular effects are mediated by a G-protein-coupled receptor mechanism, namely, G-protein-coupled estrogen receptor (GPER). Estradiol-mediated regulation of vascular cell programmed cell death reflects the balance of the opposing actions of GPER versus estrogen receptor α (ERα). However, the significance of these opposing actions on the regulation of vascular smooth muscle cell proliferation or migration in vitro is unclear, and the significance in vivo is unknown.To determine the effects of GPER activation in vitro, we studied rat aortic vascular smooth muscle cells maintained in primary culture. GPER was reintroduced using adenoviral gene transfer. Both estradiol and G1, a GPER agonist, inhibited both proliferation and cell migration effects that were blocked by the GPER antagonist, G15. To determine the importance of the GPER-ERα balance in regulating vascular remodeling in a rat model of carotid ligation, we studied the effects of upregulation of GPER expression versus downregulation of ERα. Reintroduction of GPER significantly attenuated the extent of medial hypertrophy and attenuated the extent of CD45 labeling. Downregulation of ERα expression comparably attenuated the extent of medial hypertrophy and inflammation after carotid ligation. These studies demonstrate that the balance between GPER and ERα regulates vascular remodeling. Receptor-specific modulation of estrogen's effects may be an important new approach in modifying vascular remodeling in both acute settings like vascular injury and perhaps in longer term regulation like in hypertension. Our initial focus on ERα (versus ER β , which is also expressed in rat aortic vascular smooth muscle cells [VSMCs]) was based on our demonstration that in isolated rat VSMCs, estradiol's (E2) antiapoptotic effects were mediated via ERα. 30 In contrast, E2 acting via GPER was proapoptotic. However, the in vivo implications of these receptor-specific opposing effects of estradiol on growth regulation have yet to be established.In these studies, we examined the process of vascular remodeling to understand how E2 regulates vascular growth via GPER versus ERα. Remodeling occurs subsequent to several vascular stressors including hypertension, 31 atherosclerosis, 32 and vascular injury 33 and can be associated with both adaptive responses (as in vascular injury) and maladaptive responses (as in hypertension and in vascular restenosis). The VSMC hypertrophy and hyperplasia that occurs in remodeling processes has been linked to a shift in the balance between proliferative and apoptotic mechanisms and a dedifferentiation of VSMCs from a contractile phenotype, as seen under normal conditions in situ, to a so-called synthetic phenotype, 34 as seen after vascular injury. This latter phenotype is characterized as having higher proliferative rates and greater migratory behavior. This synthetic phenotype is more similar to the phenotype of VSMCs maintained in primary culture, 35 th...

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Section: Assessment Of Regulation Of Dna Synthesis As An Index Of Promentioning

confidence: 99%

Extent of Vascular Remodeling Is Dependent on the Balance Between Estrogen Receptor α and G-Protein–Coupled Estrogen Receptor

et al. 2016

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“…Однако в данном случае процесс деградации не запускается, транс-портеры остаются в резерве около мембраны [31]. Дополнительной иллюстрацией влияния эстрадиола на серотонинергическую систему является его антиде-прессивная активность [32] и то, что G15 (антагонист GPER1) отменяет антидепрессивный эффект E 2 (и G1) в экспериментальной модели.…”

Section: эффекты эстрогенов в цнсunclassified

Estrogens and Brain

et al. 2012

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Estrogens and brain Recent data upon molecular mechanisms of pleiotropic action of estrogens in human brain is presented in the article. Given detailed descriptions of properties of classical and membrane bound estradiol receptors, that maintain gene expression regulation, modulation of neurotransmittent systems and signal cascade activation in neuronal cells. Data upon regional distribution of estradiol receptor subtypes in the brain, their participation in main cell population function control (including progenitor cells) is given. Special attention is paid to estrogen participation in neurogenesis, inflammationand apoptosis regulation in central nervous system; in the control of formation and functioning of cerebral vessels.

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“…It suggested that G-1 inhibitory effect in SKOV-3 and OVCAR-3 ovarian cancer cells due to specific activation of GPER-1 and not to cytotoxic properties. To explore the involvement of GPER-1 activation in G-1-induced cell growth inhibition we extended our experiments using G-15 a recently discovered GPER-1 receptor antagonist [21]. Pre-incubation of SKOV-3 and OVCAR-3 cells with 1 μM G-15 was able to block the inhibitory effect of G-1 ( Figure 4).…”

Section: Effect Of Gper-1 Stimulation On Ovarian Cancer Cell Prolifermentioning

confidence: 99%

GPER-1 acts as a tumor suppressor in ovarian cancer

Seiz¹,

Ignatov²,

Weißenborn³

et al. 2014

Geburtshilfe Frauenheilkd

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Background: It is known that the new membrane-bound estrogen receptor GPER-1 acts suppressive in breast cancer cells and its expression decreases during disease progression. This study was conducted to evaluate the GPER-1 expression in ovarian cancer and its correlation with progression. Its function was tested in vitro in ovarian cancer cells. Patients and methods: GPER-1 expression was analyzed by immunohistochemistry in 35 benign ovarian tumors, 35 tumors of low-malignant potential and in 124 ovarian cancers. GPER-1 expression was correlated to the prospectively evaluated disease-free survival of ovarian cancer patients. We also tested GPER-1 expression in ovarian cancer cells and the effect of GPER-1 stimulation on cell growth. Results: GPER-1 expression was significantly lower in ovarian cancer tissue than in benign and low-malignant ovarian tumors. GPER-1 expression was observed in 83.1% of malignant tumors and was higher in early stage cancers and tumors with high histological differentiation. GPER-1 expression was associated with favourable clinical outcome. The difference in 2-year disease-free survival by GPER-1 expression was significant, 28.6% for GPER-1 negative and 59.2% for GPER-1 positive cases (p = 0.002). GPER-1 expression was observed in SKOV-3 and OVCAR-3 ovarian cancer cell lines. G-1, a selective GPER-1 agonist, suppressed proliferation of the two cell types via inhibition of cell cycle progression in G2/M phase and stimulation of caspase-dependent apoptosis. The blockade in G2/M phase was associated with increased expression of cyclin B1 and Cdc2 and phosphorylation of histone 3. Conclusion: GPER-1 emerges as a new tumor suppressor with unsuspected therapeutic potential for ovarian cancer.

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In vivo effects of a GPR30 antagonist

Cited by 465 publications

References 44 publications

Extent of Vascular Remodeling Is Dependent on the Balance Between Estrogen Receptor α and G-Protein–Coupled Estrogen Receptor

Extent of Vascular Remodeling Is Dependent on the Balance Between Estrogen Receptor α and G-Protein–Coupled Estrogen Receptor

Estrogens and Brain

GPER-1 acts as a tumor suppressor in ovarian cancer

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