Differential activation of wild-type and variant forms of estrogen receptor α by synthetic and natural estrogenic compounds using a promoter containing three estrogen-responsive elements

Background The cardiovascular protective effects of estrogens in premenopausal women depend mainly on estrogen receptor α (ERα). ERα activates nuclear gene transcription regulation and membrane‐initiated signaling. The latter plays a key role in estrogen‐dependent activation of endothelial NO synthase. The goal of the present work was to determine the respective roles of the 2 ERα activities in endothelial function and cardiac and kidney damage in young and old female mice with hypertension, which is a major risk factor in postmenopausal women. Methods and Results Five‐ and 18‐month‐old female mice lacking either ERα (ERα −/− ), the nuclear activating function AF2 of ERα (AF2°), or membrane‐located ERα (C451A) were treated with angiotensin II (0.5 mg/kg per day) for 1 month. Systolic blood pressure, left ventricle weight, vascular reactivity, and kidney function were then assessed. Angiotensin II increased systolic blood pressure, ventricle weight, and vascular contractility in ERα −/− and AF2° mice more than in wild‐type and C451A mice, independent of age. In both the aorta and mesenteric resistance arteries, angiotensin II and aging reduced endothelium‐dependent relaxation in all groups, but this effect was more pronounced in ERα −/− and AF2° than in the wild‐type and C451A mice. Kidney inflammation and oxidative stress, as well as blood urea and creatinine levels, were also more pronounced in old hypertensive ERα −/− and AF2° than in old hypertensive wild‐type and C451A mice. Conclusions The nuclear ERα‐AF2 dependent function attenuates angiotensin II–dependent hypertension and protects target organs in aging mice, whereas membrane ERα signaling does not seem to play a role.

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Binding of Estrogenic Compounds to Recombinant Estrogen Receptor-α: Application to Environmental Analysis

Environmental Health Perspectives ◽

10.1289/ehp.7522 ◽

2005 ◽

Vol 113 (3) ◽

pp. 278-284 ◽

Cited By ~ 76

Author(s):

Arnaud Pillon ◽

Anne-Marie Boussioux ◽

Aurélie Escande ◽

Sélim Aït-Aïssa ◽

Elena Gomez ◽

...

Keyword(s):

Estrogen Receptor ◽

Environmental Analysis ◽

Estrogen Receptor Α ◽

Estrogenic Compounds

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Estrogen receptor-α mediates estrogen-inducible abnormalities in the developing penis

Reproduction ◽

10.1530/rep-06-0326 ◽

2007 ◽

Vol 133 (5) ◽

pp. 1057-1067 ◽

Cited By ~ 17

Author(s):

H O Goyal ◽

T D Braden ◽

P S Cooke ◽

M A Szewczykowski ◽

C S Williams ◽

...

Keyword(s):

Estrogen Receptor ◽

Levator Ani ◽

Estrogen Receptor Α ◽

Control Group ◽

Wild Type ◽

Penile Length ◽

In The Wild ◽

Os Penis ◽

Harmful Effects ◽

Wild Type Control

Previously, we reported an association between estrogen receptor-α (ERα) upregulation and detrimental effects of neonatal diethylstilbestrol (DES) exposure in the rat penis. The objective of this study was to employ the ERα knockout (ERαKO) mouse model to test the hypothesis that ERα mediates DES effects in the developing penis. ERαKO and wild-type C57BL/6 mice received oil or DES at a dose of 0.2 μg/pup per day (0.1 mg/kg) on alternate days from postnatal days 2 to 12. Fertility was tested at 80–240 days of age and tissues were examined at 96–255 days of age. DES caused malformation of the os penis, significant reductions in penile length, diameter, and weight, accumulation of fat cells in the corpora cavernosa penis, and significant reductions in weight of the bulbospongiosus and levator ani muscles in wild-type mice. Conversely, ERαKO mice treated with DES developed none of the above abnormalities. While nine out of ten male mice sired pups in the wild-type/control group, none did in the wild-type/DES group. ERαKO mice, despite normal penile development, are inherently infertile. Both plasma and intratesticular testosterone levels were unaltered in the DES-treated wild-type or DES-treated ERαKO mice when compared with controls, although testosterone concentration was much higher in the ERαKO mice. Hence, the resistance of ERαKO mice to developing penile abnormalities provides unequivocal evidence of an obligatory role for ERα in mediating the harmful effects of neonatal DES exposure in the developing penis.

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Estrogen Receptor (ER)-β Reduces ERα-Regulated Gene Transcription, Supporting a “Ying Yang” Relationship between ERα and ERβ in Mice

Molecular Endocrinology ◽

10.1210/me.2002-0206 ◽

2003 ◽

Vol 17 (2) ◽

pp. 203-208 ◽

Cited By ~ 323

Author(s):

Marie K. Lindberg ◽

Sofia Movérare ◽

Stanko Skrtic ◽

Hui Gao ◽

Karin Dahlman-Wright ◽

...

Keyword(s):

Estrogen Receptor ◽

Gene Transcription ◽

Physiological Role ◽

Estrogen Receptor Α ◽

Mrna Levels ◽

Wild Type ◽

Ovariectomized Mice ◽

Adult Bone

Abstract Estrogen is of importance for the regulation of adult bone metabolism. The aim of the present study was to determine the role of estrogen receptor-β (ERβ) in vivo on global estrogen-regulated transcriptional activity in bone. The effect of estrogen in bone of ovariectomized mice was determined using microarray analysis including 9400 genes. Most of the genes (95% = 240 genes) that were increased by estrogen in wild-type (WT) mice were also increased by estrogen in ERβ-inactivated mice. Interestingly, the average stimulatory effect of estrogen on the mRNA levels of these genes was 85% higher in ERβ-inactivated than in WT mice, demonstrating that ERβ reduces estrogen receptor-α (ERα)-regulated gene transcription in bone. The average stimulatory effect of estrogen on estrogen-regulated bone genes in ERα-inactivated mice was intermediate between that seen in WT and ERαβ double-inactivated mice. Thus, ERβ inhibits ERα-mediated gene transcription in the presence of ERα, whereas, in the absence of ERα, it can partially replace ERα. In conclusion, our in vivo data indicate that an important physiological role of ERβ is to modulate ERα-mediated gene transcription supporting a “Ying Yang” relationship between ERα and ERβ in mice.

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Tissue Distribution and Quantitative Analysis of Estrogen Receptor-α (ERα) and Estrogen Receptor-β (ERβ) Messenger Ribonucleic Acid in the Wild-Type and ERα-Knockout Mouse

Endocrinology ◽

10.1210/endo.138.11.5496 ◽

1997 ◽

Vol 138 (11) ◽

pp. 4613-4621 ◽

Cited By ~ 432

Author(s):

John F. Couse ◽

Jonathan Lindzey ◽

Kaj Grandien ◽

Jan-Åke Gustafsson ◽

Kenneth S. Korach

Keyword(s):

Estrogen Receptor ◽

Quantitative Analysis ◽

Tissue Distribution ◽

Ribonucleic Acid ◽

Knockout Mouse ◽

Estrogen Receptor Α ◽

Estrogen Receptor Β ◽

Wild Type ◽

Messenger Ribonucleic Acid ◽

In The Wild

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Coumestrol Antagonizes Neuroendocrine Actions of Estrogen via the Estrogen Receptor α

Experimental Biology and Medicine ◽

10.1177/153537020122600406 ◽

2001 ◽

Vol 226 (4) ◽

pp. 301-306 ◽

Cited By ~ 48

Author(s):

Dena A. Jacob ◽

Jennifer L. Temple ◽

Heather B. Patisaul ◽

Larry J. Young ◽

Emilie F. Rissman

Keyword(s):

Estrogen Receptor ◽

Progesterone Receptors ◽

Estrogen Receptor Α ◽

Ventromedial Nucleus ◽

Wild Type ◽

Treatment Groups ◽

Estrogenic Effects ◽

Low Levels ◽

The Brain ◽

All Treatment

The phytoestrogen coumestrol has estrogenic actions on peripheral reproductive tissues. Yet in the brain this compound has both estrogenic and anti-estrogenic effects. We used estrogen receptor α knockout mice (ERαKO) to determine whether coumestrol has estrogenic actions in mice and also if these effects are mediated by the classic ERα. Female wild-type (WT) and ERαKO mice were ovariectomized and treated with estradiol (E2), dietary coumestrol, both, or neither compound. Ten days later the animals were sacrificed, blood was collected, and brain tissues were perfused. Fixed brains were sectioned and immunocytochemistry was employed to quantify progesterone receptors (PR) in the medial preoptic (POA) and ventromedial nucleus of the hypothalamus (VMN). Plasma was assayed for luteinizing hormone (LH). Estrogen treatment induced PR immunoreactivity in both regions in brains of WT females. In ERαKO mice, lower levels of PR were induced. The stimulatory effects of E2 on PR were attenuated in the POA by cotreatment with coumestrol, and the same trend was noted in the VMN. WT ovariectomized females treated with E2 had low levels of LH, while LH was high in untreated females and even higher in ovariectomized females treated with coumestrol. ERαKO females in all treatment groups had high levels of LH. Taken together, the results show that coumestrol has anti-estrogenic actions in the brain and pituitary and that ERα mediates these effects.

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Transcription and Translation of Estrogen Receptor-β in the Male Reproductive Tract of Estrogen Receptor-α Knock-Out and Wild-Type Mice1

Endocrinology ◽

10.1210/endo.139.6.6028 ◽

1998 ◽

Vol 139 (6) ◽

pp. 2982-2987 ◽

Cited By ~ 54

Author(s):

Cheryl S. Rosenfeld ◽

Venkataseshu K. Ganjam ◽

Julia A. Taylor ◽

Xiaohui Yuan ◽

James R. Stiehr ◽

...

Keyword(s):

Estrogen Receptor ◽

Reproductive Tract ◽

Estrogen Receptor Α ◽

Estrogen Receptor Β ◽

Wild Type ◽

Male Reproductive Tract ◽

Knock Out

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Estrogen Receptor-α Signaling in Growth of the Ventral Prostate: Comparison of Neonatal Growth and Postcastration Regrowth

Endocrinology ◽

10.1210/en.2007-1413 ◽

2008 ◽

Vol 149 (9) ◽

pp. 4421-4427 ◽

Cited By ~ 11

Author(s):

Yoko Omoto

Keyword(s):

Estrogen Receptor ◽

Cyclin D1 ◽

Branching Morphogenesis ◽

Estrogen Receptor Α ◽

Testosterone Replacement ◽

Ventral Prostate ◽

Wild Type ◽

Fibroblast Growth Factor 10 ◽

Ductal Branching ◽

Stimulation Of

A role for estrogen receptor (ER)-α in branching morphogenesis in the ventral prostate (VP) has previously been demonstrated; in the VP of ERα−/− mice, there are fewer side branches than in wild-type littermates. In the present study, we show that in the postnatal VP, fibroblast growth factor 10 (FGF10) is expressed in wild-type mice but not in ERα−/− mice, and because branching involves proliferation pathways also used in malignant growth, we investigated whether branching during regrowth of the VP after castration involves ERα and FGF10. ERα was not detectable in the prostates of sham-operated or castrated mice but was expressed in the prostatic epithelium between d 3 and 5 after testosterone replacement. Blocking either ERα or ERβ with ICI 182,780 had no detectable effects on epithelial cell proliferation during regrowth by testosterone. The ERα agonist, propylpyrazoletriol, did not induce regrowth by itself, but exposure to propylpyrazoletriol on d 3–5 of testosterone replacement resulted in cyclin D1-positive cells in the ductal epithelium, invasion of FGF10-positive immune cells in the regrowing prostate, and budding 14 d later. Testosterone replacement alone did not induce cyclin D1, FGF10, or bud formation. These results indicate that stimulation of ERα is essential for ductal branching during postnatal prostate growth. During regrowth after castration, there is a window in time when selective stimulation of ERα can also induce ductal branching. The FGF10 for this growth comes from the immune system, not from the prostatic mesenchyme.

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