2-Methoxyestradiol, an endogenous 17β-estradiol metabolite, inhibits microglial proliferation and activation via an estrogen receptor-independent mechanism

Schaufelberger, Sara; Rosselli, Marinella; Barchiesi, Federica; Gillespie, Delbert G.; Jackson, Edwin K.; Dubey, Raghvendra K.

doi:10.1152/ajpendo.00418.2015

Cited by 27 publications

(11 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, the effect of 2-ME to inhibit vascular smooth muscle cell migration and proliferation and microglial cell BV2 proliferation and the process of phagocytosis were shown to be independent of estrogen or GPER1 receptors. 38 In our study in Cyp1b1 +/+ female mice, where Ang II increased plasma and urinary 2-ME levels, 15,16 the selective GPER1 receptor antagonist G15 reduced heart:body weight ratio but failed to alter the effect Ang II to increase SBP, heart:body weight ratio, water intake or urine output. The decrease in heart weight produced by G15 is most likely due to a decrease in body weight.…”

Section: Discussionmentioning

confidence: 58%

2-Methoxyestradiol Reduces Angiotensin II–Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice

et al. 2017

View full text Add to dashboard Cite

cytochrome P45 1B1 protects against angiotensin II-induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol. This study was conducted to determine if 2-methoxyestradiol ameliorates angiotensin II-induced hypertension, renal dysfunction, and end-organ damage in intact Cyp1b1−/−, ovariectomized female, and in Cyp1b1+/+ male mice. Ang II or vehicle was infused for 2 weeks and administered concurrently with 2-methoxyestradiol. Mice were placed in metabolic cages on day 12 of Ang II infusion for urine collection for 24 h. 2-Methoxyestradiol reduced angiotensin II-induced increases in systolic blood pressure, water consumption, urine output, and proteinuria in intact female Cyp1b1−/− and ovariectomized mice. 2-Methoxyestradiol also reduced Ang II-induced increase in blood pressure, water intake, urine output, and proteinuria in Cyp1b1+/+ male mice. Treatment with 2-methoxyestradiol attenuated Ang II-induced end-organ damage in intact Cyp1b1−/− and ovariectomized Cyp1b1+/+ and Cyp1b1−/− female mice, and Cyp1b1+/+ male mice. 2-Methoxyestradiol mitigated Ang II-induced increase in urinary excretion of angiotensinogen in intact Cyp1b1−/− and ovariectomized Cyp1b1+/+ and Cyp1b1−/− female mice but not in Cyp1b1+/+ male mice. The G-protein-coupled estrogen receptor 1 antagonist G-15 failed to alter Ang II-induced increases in blood pressure and renal function in Cyp1b1+/+ female mice. These data suggest that 2-methoxyestradiol reduces angiotensin II-induced hypertension and associated end-organ damage in intact Cyp1b1−/−, ovariectomized Cyp1b1+/+ and Cyp1b1−/− female mice, and Cyp1b1+/+ male mice independent of G protein-coupled estrogen receptor 1. Therefore, 2-methoxyestradiol could serve as a therapeutic agent for treating hypertension and associated pathogenesis in postmenopausal females, and in males.

show abstract

Section: Discussionmentioning

confidence: 58%

2-Methoxyestradiol Reduces Angiotensin II–Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The discovery of GPER1 shed a new light on the effect of estrogen in neuro-inflammation. Indeed, GPER1 was found, in addition to neuronal cells ( 61 ), also on microglial cells and astrocytes ( 63 – 67 ). Anti-inflammatory effects were attributed to GPER1 in several systems, including cells of the CNS ( 1 , 8 , 27 , 61 , 62 , 66 – 71 ).…”

Section: Gper1 Involvement In Immune-related Human Diseasesmentioning

confidence: 99%

G Protein-Coupled Estrogen Receptor in Immune Cells and Its Role in Immune-Related Diseases

2020

View full text Add to dashboard Cite

G protein-coupled estrogen receptor 1 (GPER1), is a functional estrogen receptor involved in estrogen related actions on several systems including processes of the nervous, reproductive, metabolic, cardiovascular, and immune system. Regarding the latter, GPER is expressed in peripheral B and T lymphocytes as well as in monocytes, eosinophils, and neutrophils. Several studies have implicated GPER in immune-mediated diseases like multiple sclerosis, Parkinson’s disease, and atherosclerosis-related inflammation, while a recent report suggests that its deletion could be responsible for a form of familial immunodeficiency. It has also been suggested that it is a key regulator of immune-mediated events in breast, pancreatic, prostate, and hepatocellular cancer as well as in melanoma. GPER has been also reported to interact with classic ER-alpha or its splice variants in order to modify immune functions. This review aims to present current knowledge relating GPER to immune functions, the cellular and signaling pathways involved, as well as the potential clinical implications of GPER modulation in immune-related diseases.

show abstract

“…In this regard, 2ME binds the membrane GPER and, via GPER-mediated transactivation of EGFR and ERK1/2 phosphorylation, downregulates AT1 receptor expression [90,91]. Yet, the antimitogenic effects of 2ME in microglia cells and vascular smooth muscle cells (VSMCs) are independent of GPER or nuclear E2 receptors [112]. Whether cardiovascular protective effects of 2ME are mediated by GPER remains to be determined.…”

Section: Other Effects Of the 2-methylation Pathway Relevant To Pahmentioning

confidence: 99%

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

Tofovic

Jackson

2019

IJMS

Self Cite

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is a debilitating and progressive disease that predominantly develops in women. Over the past 15 years, cumulating evidence has pointed toward dysregulated metabolism of sex hormones in animal models and patients with PAH. 17β-estradiol (E2) is metabolized at positions C2, C4, and C16, which leads to the formation of metabolites with different biological/estrogenic activity. Since the first report that 2-methoxyestradiol, a major non-estrogenic metabolite of E2, attenuates the development and progression of experimental pulmonary hypertension (PH), it has become increasingly clear that E2, E2 precursors, and E2 metabolites exhibit both protective and detrimental effects in PH. Furthermore, both experimental and clinical data suggest that E2 has divergent effects in the pulmonary vasculature versus right ventricle (estrogen paradox in PAH). The estrogen paradox is of significant clinical relevance for understanding the development, progression, and prognosis of PAH. This review updates experimental and clinical findings and provides insights into: (1) the potential impacts that pathways of estradiol metabolism (EMet) may have in PAH; (2) the beneficial and adverse effects of estrogens and their precursors/metabolites in experimental PH and human PAH; (3) the co-morbidities and pathological conditions that may alter EMet and influence the development/progression of PAH; (4) the relevance of the intracrinology of sex hormones to vascular remodeling in PAH; and (5) the advantages/disadvantages of different approaches to modulate EMet in PAH. Finally, we propose the three-tier-estrogen effects in PAH concept, which may offer reconciliation of the opposing effects of E2 in PAH and may provide a better understanding of the complex mechanisms by which EMet affects the pulmonary circulation–right ventricular interaction in PAH.

show abstract

2-Methoxyestradiol, an endogenous 17β-estradiol metabolite, inhibits microglial proliferation and activation via an estrogen receptor-independent mechanism

Cited by 27 publications

References 41 publications

2-Methoxyestradiol Reduces Angiotensin II–Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice

2-Methoxyestradiol Reduces Angiotensin II–Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice

G Protein-Coupled Estrogen Receptor in Immune Cells and Its Role in Immune-Related Diseases

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

Contact Info

Product

Resources

About