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1. Membrane estrogen receptor-α contributes to female protection against high-fat diet-induced metabolic disorders

Author

Aurélie Fabre, Blandine Tramunt, Alexandra Montagner, Céline Mouly, Elodie Riant, Marie-Lou Calmy, Marine Adlanmerini, Coralie Fontaine, Rémy Burcelin, Françoise Lenfant, Jean-François Arnal, and Pierre Gourdy

Subjects
sex differences, estrogen receptor alpha (ERα), membrane-initiated steroid signaling, obesity, insulin resistance, thermogenesis, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

BackgroundEstrogen Receptor α (ERα) is a significant modulator of energy balance and lipid/glucose metabolisms. Beyond the classical nuclear actions of the receptor, rapid activation of intracellular signaling pathways is mediated by a sub-fraction of ERα localized to the plasma membrane, known as Membrane Initiated Steroid Signaling (MISS). However, whether membrane ERα is involved in the protective metabolic actions of endogenous estrogens in conditions of nutritional challenge, and thus contributes to sex differences in the susceptibility to metabolic diseases, remains to be clarified.MethodsMale and female C451A-ERα mice, harboring a point mutation which results in the abolition of membrane localization and MISS-related effects of the receptor, and their wild-type littermates (WT-ERα) were maintained on a normal chow diet (NCD) or fed a high-fat diet (HFD). Body weight gain, body composition and glucose tolerance were monitored. Insulin sensitivity and energy balance regulation were further investigated in HFD-fed female mice.ResultsC451A-ERα genotype had no influence on body weight gain, adipose tissue accumulation and glucose tolerance in NCD-fed mice of both sexes followed up to 7 months of age, nor male mice fed a HFD for 12 weeks. In contrast, compared to WT-ERα littermates, HFD-fed C451A-ERα female mice exhibited: 1) accelerated fat mass accumulation, liver steatosis and impaired glucose tolerance; 2) whole-body insulin resistance, assessed by hyperinsulinemic-euglycemic clamps, and altered insulin-induced signaling in skeletal muscle and liver; 3) significant decrease in energy expenditure associated with histological and functional abnormalities of brown adipose tissue and a defect in thermogenesis regulation in response to cold exposure.ConclusionBesides the well-characterized role of ERα nuclear actions, membrane-initiated ERα extra-nuclear signaling contributes to female, but not to male, protection against HFD-induced obesity and associated metabolic disorders in mouse.

Published
2023
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2. The different natural estrogens promote endothelial healing through distinct cell targets

Author

Morgane Davezac, Rana Zahreddine, Melissa Buscato, Natalia F. Smirnova, Chanaelle Febrissy, Henrik Laurell, Silveric Gilardi-Bresson, Marine Adlanmerini, Philippe Liere, Gilles Flouriot, Rachida Guennoun, Muriel Laffargue, Jean-Michel Foidart, Françoise Lenfant, Jean-François Arnal, Raphaël Métivier, and Coralie Fontaine

Subjects
Endocrinology, Vascular biology, Medicine
Abstract

The main estrogen, 17β-estradiol (E2), exerts several beneficial vascular actions through estrogen receptor α (ERα) in endothelial cells. However, the impact of other natural estrogens such as estriol (E3) and estetrol (E4) on arteries remains poorly described. In the present study, we report the effects of E3 and E4 on endothelial healing after carotid artery injuries in vivo. After endovascular injury, which preserves smooth muscle cells (SMCs), E2, E3, and E4 equally stimulated reendothelialization. By contrast, only E2 and E3 accelerated endothelial healing after perivascular injury that destroys both endothelial cells and SMCs, suggesting an important role of this latter cell type in E4’s action, which was confirmed using Cre/lox mice inactivating ERα in SMCs. In addition, E4 mediated its effects independently of ERα membrane-initiated signaling, in contrast with E2. Consistently, RNA sequencing analysis revealed that transcriptomic and cellular signatures in response to E4 profoundly differed from those of E2. Thus, whereas acceleration of endothelial healing by estrogens had been viewed as entirely dependent on endothelial ERα, these results highlight the very specific pharmacological profile of the natural estrogen E4, revealing the importance of dialogue between SMCs and endothelial cells in its arterial protection.

Published
2023
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3. Estrogen Actions in Placental Vascular Morphogenesis and Spiral Artery Remodeling: A Comparative View between Humans and Mice

Author

Mariam Rusidzé, Adrien Gargaros, Chanaëlle Fébrissy, Charlotte Dubucs, Ariane Weyl, Jessie Ousselin, Jacqueline Aziza, Jean-François Arnal, and Françoise Lenfant

Subjects
placentation, trophoblasts, spiral artery remodeling, angiogenesis, hemodynamics, estrogen receptor, Cytology, QH573-671
Abstract

Estrogens, mainly 17β-estradiol (E2), play a critical role in reproductive organogenesis, ovulation, and fertility via estrogen receptors. E2 is also a well-known regulator of utero-placental vascular development and blood-flow dynamics throughout gestation. Mouse and human placentas possess strikingly different morphological configurations that confer important reproductive advantages. However, the functional interplay between fetal and maternal vasculature remains similar in both species. In this review, we briefly describe the structural and functional characteristics, as well as the development, of mouse and human placentas. In addition, we summarize the current knowledge regarding estrogen actions during utero-placental vascular morphogenesis, which includes uterine angiogenesis, the control of trophoblast behavior, spiral artery remodeling, and hemodynamic adaptation throughout pregnancy, in both mice and humans. Finally, the estrogens that are present in abnormal placentation are also mentioned. Overall, this review highlights the importance of the actions of estrogens in the physiology and pathophysiology of placental vascular development.

Published
2023
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4. Membrane estrogen receptor alpha (ERα) participates in flow-mediated dilation in a ligand-independent manner

Author

Julie Favre, Emilie Vessieres, Anne-Laure Guihot, Coralyne Proux, Linda Grimaud, Jordan Rivron, Manuela CL Garcia, Léa Réthoré, Rana Zahreddine, Morgane Davezac, Chanaelle Fébrissy, Marine Adlanmerini, Laurent Loufrani, Vincent Procaccio, Jean-Michel Foidart, Gilles Flouriot, Françoise Lenfant, Coralie Fontaine, Jean-François Arnal, and Daniel Henrion

Subjects
endothelium, shear stress, estrogen receptors, blood flow, resistance arteries, Medicine, Science, Biology (General), QH301-705.5
Abstract

Estrogen receptor alpha (ERα) activation by estrogens prevents atheroma through its nuclear action, whereas plasma membrane-located ERα accelerates endothelial healing. The genetic deficiency of ERα was associated with a reduction in flow-mediated dilation (FMD) in one man. Here, we evaluated ex vivo the role of ERα on FMD of resistance arteries. FMD, but not agonist (acetylcholine, insulin)-mediated dilation, was reduced in male and female mice lacking ERα (Esr1-/- mice) compared to wild-type mice and was not dependent on the presence of estrogens. In C451A-ERα mice lacking membrane ERα, not in mice lacking AF2-dependent nuclear ERα actions, FMD was reduced, and restored by antioxidant treatments. Compared to wild-type mice, isolated perfused kidneys of C451A-ERα mice revealed a decreased flow-mediated nitrate production and an increased H2O2 production. Thus, endothelial membrane ERα promotes NO bioavailability through inhibition of oxidative stress and thereby participates in FMD in a ligand-independent manner.

Published
2021
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5. Selective Liver Estrogen Receptor α Modulation Prevents Steatosis, Diabetes, and Obesity Through the Anorectic Growth Differentiation Factor 15 Hepatokine in Mice

Author

Maeva Guillaume, Elodie Riant, Aurélie Fabre, Isabelle Raymond‐Letron, Melissa Buscato, Morgane Davezac, Blandine Tramunt, Alexandra Montagner, Sarra Smati, Rana Zahreddine, Gaëlle Palierne, Marie‐Cécile Valera, Hervé Guillou, Françoise Lenfant, Klaus Unsicker, Raphaël Metivier, Coralie Fontaine, Jean‐François Arnal, and Pierre Gourdy

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Hepatocyte estrogen receptor α (ERα) was recently recognized as a relevant molecular target for nonalcoholic fatty liver disease (NAFLD) prevention. The present study defined to what extent hepatocyte ERα could be involved in preserving metabolic homeostasis in response to a full (17β‐estradiol [E2]) or selective (selective estrogen receptor modulator [SERM]) activation. Ovariectomized mice harboring a hepatocyte‐specific ERα deletion (LERKO mice) and their wild‐type (WT) littermates were fed a high‐fat diet (HFD) and concomitantly treated with E2, tamoxifen (TAM; the most used SERM), or vehicle. As expected, both E2 and TAM prevented all HFD‐induced metabolic disorders in WT mice, and their protective effects against steatosis were abolished in LERKO mice. However, while E2 still prevented obesity and glucose intolerance in LERKO mice, hepatocyte ERα deletion also abrogated TAM‐mediated control of food intake as well as its beneficial actions on adiposity, insulin sensitivity, and glucose homeostasis, suggesting a whole‐body protective role for liver‐derived circulating factors. Moreover, unlike E2, TAM induced a rise in plasma concentration of the anorectic hepatokine growth differentiation factor 15 (Gdf15) through a transcriptional mechanism dependent on hepatocyte ERα activation. Accordingly, ERα was associated with specific binding sites in the Gdf15 regulatory region in hepatocytes from TAM‐treated mice but not under E2 treatment due to specific epigenetic modifications. Finally, all the protective effects of TAM were abolished in HFD‐fed GDF15‐knockout mice. Conclusion: We identified the selective modulation of hepatocyte ERα as a pharmacologic strategy to induce sufficient anorectic hepatokine Gdf15 to prevent experimental obesity, type 2 diabetes, and NAFLD.

Published
2019
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6. Effects of conjugated estrogen and bazedoxifene on hemostasis and thrombosis in mice

Author

Emmanuelle Noirrit, Mélissa Buscato, Marion Dupuis, Bernard Payrastre, Coralie Fontaine, Jean-François Arnal, and Marie-Cécile Valera

Subjects
bazedoxifene, tissue-selective estrogen complex (TSEC), thrombosis, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Estrogen–progestin therapy was previously considered as the standard of care for managing bothersome symptoms associated with menopause, but it increases risks of breast cancer and of thromboembolism. The combination of conjugated estrogen (CE) with bazedoxifene (BZA) named tissue-selective estrogen complex (TSEC) was designed to minimize or even abrogate the undesirable effects on breast, while maintaining the beneficial effects such as prevention of osteoporosis and suppression of climacteric symptoms. The risk on thromboembolism associated with TSEC is unknown, although the clinical available data are reassuring. The aim of this study was to define the impact of a chronic administration of CE, BZA or CE + BZA on hemostasis and thrombosis in ovariectomized mice. As expected, CE, but not BZA neither CE + BZA, induced uterine and vagina hypertrophy. As previously demonstrated for 17β-estradiol (E2), we found that CE (i) increased tail-bleeding time, (ii) prevented occlusive thrombus formation in injured carotid artery and (iii) protected against collagen/epinephrine-induced thromboembolism. Thus, whereas BZA antagonized CE action on reproductive tissues, it had no impact on the effect of CE on hemostasis, thromboembolism and arterial thrombosis in mice. CE + BZA shared the anti-thrombotic actions of CE in these mouse models. If a similar process is at work in women, CE combined with BZA could contribute to minimize the risk of thrombosis associated with hormone replacement therapy.

Published
2019
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7. Nuclear Activation Function 2 Estrogen Receptor α Attenuates Arterial and Renal Alterations Due to Aging and Hypertension in Female Mice

Author

Emmanuel Guivarc'h, Julie Favre, Anne‐Laure Guihot, Emilie Vessières, Linda Grimaud, Coralyne Proux, Jordan Rivron, Agnès Barbelivien, Céline Fassot, Marie Briet, Françoise Lenfant, Coralie Fontaine, Laurent Loufrani, Jean‐François Arnal, and Daniel Henrion

Subjects
aging, endothelium, estrogen, hypertension, kidney, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

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.

Published
2020
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8. Estrogen receptor subcellular localization and cardiometabolism

Author

Pierre Gourdy, Maeva Guillaume, Coralie Fontaine, Marine Adlanmerini, Alexandra Montagner, Henrik Laurell, Françoise Lenfant, and Jean-François Arnal

Subjects
Internal medicine, RC31-1245
Abstract

Background: In addition to their crucial role in reproduction, estrogens are key regulators of energy and glucose homeostasis and they also exert several cardiovascular protective effects. These beneficial actions are mainly mediated by estrogen receptor alpha (ERα), which is widely expressed in metabolic and vascular tissues. As a member of the nuclear receptor superfamily, ERα was primarily considered as a transcription factor that controls gene expression through the activation of its two activation functions (ERαAF-1 and ERαAF-2). However, besides these nuclear actions, a pool of ERα is localized in the vicinity of the plasma membrane, where it mediates rapid signaling effects called membrane-initiated steroid signals (MISS) that have been well described in vitro, especially in endothelial cells. Scope of the review: This review aims to summarize our current knowledge of the mechanisms of nuclear vs membrane ERα activation that contribute to the cardiometabolic protection conferred by estrogens. Indeed, new transgenic mouse models (affecting either DNA binding, activation functions or membrane localization), together with the use of novel pharmacological tools that electively activate membrane ERα effects recently allowed to begin to unravel the different modes of ERα signaling in vivo. Conclusion: Altogether, available data demonstrate the prominent role of ERα nuclear effects, and, more specifically, of ERαAF-2, in the preventive effects of estrogens against obesity, diabetes, and atheroma. However, membrane ERα signaling selectively mediates some of the estrogen endothelial/vascular effects (NO release, reendothelialization) and could also contribute to the regulation of energy balance, insulin sensitivity, and glucose metabolism. Such a dissection of ERα biological functions related to its subcellular localization will help to understand the mechanism of action of “old” ER modulators and to design new ones with an optimized benefit/risk profile. Keywords: Estrogen receptors, Genomic effects, Membrane-initiated steroid signals, Energy balance, Glucose homeostasis, Cardiovascular system

Published
2018
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9. Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety

Author

Emmanuel Guivarc'h, Mélissa Buscato, Anne‐Laure Guihot, Julie Favre, Emilie Vessières, Linda Grimaud, Jamal Wakim, Nada‐Joe Melhem, Rana Zahreddine, Marine Adlanmerini, Laurent Loufrani, Claude Knauf, John A. Katzenellenbogen, Benita S. Katzenellenbogen, Jean‐Michel Foidart, Pierre Gourdy, Françoise Lenfant, Jean‐François Arnal, Daniel Henrion, and Coralie Fontaine

Subjects
arteriolar remodeling, atherosclerosis, estrogen, hypertension, nuclear receptor, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background Although estrogen receptor α (ERα) acts primarily as a transcription factor, it can also elicit membrane‐initiated steroid signaling. Pharmacological tools and transgenic mouse models previously highlighted the key role of ERα membrane‐initiated steroid signaling in 2 actions of estrogens in the endothelium: increase in NO production and acceleration of reendothelialization. Methods and Results Using mice with ERα mutated at cysteine 451 (ERaC451A), recognized as the key palmitoylation site required for ERα plasma membrane location, and mice with disruption of nuclear actions because of inactivation of activation function 2 (ERaAF20 = ERaAF2°), we sought to fully characterize the respective roles of nuclear versus membrane‐initiated steroid signaling in the arterial protection conferred by ERα. ERaC451A mice were fully responsive to estrogens to prevent atheroma and angiotensin II–induced hypertension as well as to allow flow‐mediated arteriolar remodeling. By contrast, ERαAF20 mice were unresponsive to estrogens for these beneficial vascular effects. Accordingly, selective activation of nuclear ERα with estetrol was able to prevent hypertension and to restore flow‐mediated arteriolar remodeling. Conclusions Altogether, these results reveal an unexpected prominent role of nuclear ERα in the vasculoprotective action of estrogens with major implications in medicine, particularly for selective nuclear ERα agonist, such as estetrol, which is currently under development as a new oral contraceptive and for hormone replacement therapy in menopausal women.

Published
2018
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10. Effect of chronic estradiol plus progesterone treatment on experimental arterial and venous thrombosis in mouse.

Author

Marie-Cécile Valéra, Emmanuelle Noirrit-Esclassan, Marion Dupuis, Melissa Buscato, Alexia Vinel, Maeva Guillaume, Anne Briaux, Cédric Garcia, Thibaut Benoit, Olivier Lairez, Coralie Fontaine, Bernard Payrastre, and Jean-François Arnal

Subjects
Medicine, Science
Abstract

Postmenopausal hormone replacement therapy (HRT) with estrogen plus progestogens is the first line therapy to treat menopausal symptoms. The progestogen is added to estrogen to reduce or eliminate the excess risk of endometrial cancer due to the unopposed effect of estrogen. Whereas progestin clearly opposes the proliferative and deleterious long-term actions of estrogen on the endometrium, the interference of progestin on the other estrogen action remains unclear. We previously reported that chronic subcutaneous 17α-estradiol (E2) in mice decreases platelet responsiveness, prolongs the tail-bleeding time and protects against acute thromboembolism. Here, we report the tissue-specific interference of progesterone (P4) on the action of E2 in ovariectomized mice. We first confirm that, in our experimental conditions, P4 attenuates the proliferative action of E2 on the uterus and the effects of E2 on vagina weight and lubrication. We then studied the effect of E2 combined with P4 on hemostasis and thrombosis in vivo in mice and found that P4 did not interfere with the main actions of E2 on platelets, bleeding time and arterial and venous thrombosis. Thus, whereas activation of progesterone receptor interferes with the action of E2 on its classic sex targets, P4 appears to have minimal effect on the hemostasis and thrombosis actions of E2, supporting the prominent role of estrogens and the accessory role of natural progestin on the extra-reproductive cells and tissues involved in thrombosis.

Published
2017
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11. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation

Author

Anne Abot, Coralie Fontaine, Mélissa Buscato, Romain Solinhac, Gilles Flouriot, Aurélie Fabre, Anne Drougard, Shyamala Rajan, Muriel Laine, Alain Milon, Isabelle Muller, Daniel Henrion, Marine Adlanmerini, Marie‐Cécile Valéra, Anne Gompel, Céline Gerard, Christel Péqueux, Mélanie Mestdagt, Isabelle Raymond‐Letron, Claude Knauf, François Ferriere, Philippe Valet, Pierre Gourdy, Benita S Katzenellenbogen, John A Katzenellenbogen, Françoise Lenfant, Geoffrey L Greene, Jean‐Michel Foidart, and Jean‐François Arnal

Subjects
endothelium, estetrol, estrogen receptor, uterus, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Estetrol (E4) is a natural estrogen with a long half‐life produced only by the human fetal liver during pregnancy. The crystal structures of the estrogen receptor α (ERα) ligand‐binding domain bound to 17β‐estradiol (E2) and E4 are very similar, as well as their capacity to activate the two activation functions AF‐1 and AF‐2 and to recruit the coactivator SRC3. In vivo administration of high doses of E4 stimulated uterine gene expression, epithelial proliferation, and prevented atheroma, three recognized nuclear ERα actions. However, E4 failed to promote endothelial NO synthase activation and acceleration of endothelial healing, two processes clearly dependent on membrane‐initiated steroid signaling (MISS). Furthermore, E4 antagonized E2 MISS‐dependent effects in endothelium but also in MCF‐7 breast cancer cell line. This profile of ERα activation by E4, uncoupling nuclear and membrane activation, characterizes E4 as a selective ER modulator which could have medical applications that should now be considered further.

Published
2014
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12. Resveratrol Improved Flow-Mediated Outward Arterial Remodeling in Ovariectomized Rats with Hypertrophic Effect at High Dose.

Author

Marie Petit, Anne-Laure Guihot, Linda Grimaud, Emilie Vessieres, Bertrand Toutain, Marie-Claude Menet, Valérie Nivet-Antoine, Jean-François Arnal, Laurent Loufrani, Vincent Procaccio, and Daniel Henrion

Subjects
Medicine, Science
Abstract

OBJECTIVES:Chronic increases in blood flow in resistance arteries induce outward remodeling associated with increased wall thickness and endothelium-mediated dilatation. This remodeling is essential for collateral arteries growth following occlusion of a large artery. As estrogens have a major role in this remodeling, we hypothesized that resveratrol, described as possessing phytoestrogen properties, could improve remodeling in ovariectomized rats. METHODS:Blood flow was increased in vivo in mesenteric arteries after ligation of adjacent arteries in 3-month old ovariectomized rats treated with resveratrol (5 or 37.5 mg/kg per day: RESV5 or RESV37.5) or vehicle. After 2 weeks arterial structure and function were measured in vitro in high flow (HF) and normal flow (NF) arteries isolated from each rat. RESULTS:Arterial diameter was greater in HF than in NF arteries in ovariectomized rats treated with RESV5 or RESV37.5, not in vehicle-treated rats. In mice lacking estrogen receptor alpha diameter was equivalent in HF and NF arteries whereas in mice treated with RESV5 diameter was greater in HF than in NF vessels. A compensatory increase in wall thickness and a greater phenylephrine-mediated contraction were observed in HF arteries. This was more pronounced in HF arteries from RESV37.5-treated rats. ERK1/2 phosphorylation, involved in hypertrophy and contraction, were higher in RESV37.5-treated rats than in RESV5- and vehicle-treated rats. Endothelium-dependent relaxation was greater in HF than in NF arteries in RESV5-treated rats only. In HF arteries from RESV37.5-treated rats relaxation was increased by superoxide reduction and markers of oxidative stress (p67phox, GP91phox) were higher than in the 2 other groups. CONCLUSION:Resveratrol improved flow-mediated outward remodeling in ovariectomized rats thus providing a potential therapeutic tool in menopause-associated ischemic disorders. This effect seems independent of the estrogen receptor alpha. Nevertheless, caution should be taken with high doses inducing excessive contractility and hypertrophy in association with oxidative stress in HF arteries.

Published
2016
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14. High-fat diet induces periodontitis in mice through lipopolysaccharides (LPS) receptor signaling: protective action of estrogens.

Author

Vincent Blasco-Baque, Matteo Serino, Jean-Noël Vergnes, Elodie Riant, Pascale Loubieres, Jean-François Arnal, Pierre Gourdy, Michel Sixou, Rémy Burcelin, and Philippe Kemoun

Subjects
Medicine, Science
Abstract

BackgroundA fat-enriched diet favors the development of gram negative bacteria in the intestine which is linked to the occurrence of type 2 diabetes (T2D). Interestingly, some pathogenic gram negative bacteria are commonly associated with the development of periodontitis which, like T2D, is characterized by a chronic low-grade inflammation. Moreover, estrogens have been shown to regulate glucose homeostasis via an LPS receptor dependent immune-modulation. In this study, we evaluated whether diet-induced metabolic disease would favor the development of periodontitis in mice. In addition, the regulatory role of estrogens in this process was assessed.MethodsFour-week-old C57BL6/J WT and CD14 (part of the TLR-4 machinery for LPS-recognition) knock-out female mice were ovariectomised and subcutaneously implanted with pellets releasing either placebo or 17β-estradiol (E2). Mice were then fed with either a normal chow or a high-fat diet for four weeks. The development of diabetes was monitored by an intraperitoneal glucose-tolerance test and plasma insulin concentration while periodontitis was assessed by identification of pathogens, quantification of periodontal soft tissue inflammation and alveolar bone loss.ResultsThe fat-enriched diet increased the prevalence of periodontal pathogenic microbiota like Fusobacterium nucleatum and Prevotella intermedia, gingival inflammation and alveolar bone loss. E2 treatment prevented this effect and CD14 knock-out mice resisted high-fat diet-induced periodontal defects.Conclusions/significanceOur data show that mice fed with a diabetogenic diet developed defects and microflora of tooth supporting-tissues typically associated with periodontitis. Moreover, our results suggest a causal link between the activation of the LPS pathway on innate immunity by periodontal microbiota and HFD-induced periodontitis, a pathophysiological mechanism that could be targeted by estrogens.

Published
2012
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15. Estrogen receptor alpha as a key target of red wine polyphenols action on the endothelium.

Author

Matthieu Chalopin, Angela Tesse, Maria Carmen Martínez, Didier Rognan, Jean-François Arnal, and Ramaroson Andriantsitohaina

Subjects
Medicine, Science
Abstract

BACKGROUND: A greater reduction in cardiovascular risk and vascular protection associated with diet rich in polyphenols are generally accepted; however, the molecular targets for polyphenols effects remain unknown. Meanwhile evidences in the literature have enlightened, not only structural similarities between estrogens and polyphenols known as phytoestrogens, but also in their vascular effects. We hypothesized that alpha isoform of estrogen receptor (ERalpha) could be involved in the transduction of the vascular benefits of polyphenols. METHODOLOGY/PRINCIPAL FINDINGS: Here, we used ERalpha deficient mice to show that endothelium-dependent vasorelaxation induced either by red wine polyphenol extract, Provinols, or delphinidin, an anthocyanin that possesses similar pharmacological profile, is mediated by ERalpha. Indeed, Provinols, delphinidin and ERalpha agonists, 17-beta-estradiol and PPT, are able to induce endothelial vasodilatation in aorta from ERalpha Wild-Type but not from Knock-Out mice, by activation of nitric oxide (NO) pathway in endothelial cells. Besides, silencing the effects of ERalpha completely prevented the effects of Provinols and delphinidin to activate NO pathway (Src, ERK 1/2, eNOS, caveolin-1) leading to NO production. Furthermore, direct interaction between delphinidin and ERalpha activator site is demonstrated using both binding assay and docking. Most interestingly, the ability of short term oral administration of Provinols to decrease response to serotonin and to enhance sensitivity of the endothelium-dependent relaxation to acetylcholine, associated with concomitant increased NO production and decreased superoxide anions, was completely blunted in ERalpha deficient mice. CONCLUSIONS/SIGNIFICANCE: This study provides evidence that red wine polyphenols, especially delphinidin, exert their endothelial benefits via ERalpha activation. It is a major breakthrough bringing new insights of the potential therapeutic of polyphenols against cardiovascular pathologies.

Published
2010
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16. FGF2 translationally induced by hypoxia is involved in negative and positive feedback loops with HIF-1alpha.

Author

Caroline Conte, Elodie Riant, Céline Toutain, Françoise Pujol, Jean-François Arnal, Françoise Lenfant, and Anne-Catherine Prats

Subjects
Medicine, Science
Abstract

BACKGROUND: Fibroblast growth factor 2 (FGF2) is a major angiogenic factor involved in angiogenesis and arteriogenesis, however the regulation of its expression during these processes is poorly documented. FGF2 mRNA contains an internal ribosome entry site (IRES), a translational regulator expected to allow mRNA expression during cellular stress. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we have developed a skin ischemia model in transgenic mice expressing a reporter transgene under the control of the FGF2 IRES. The results reveal that FGF2 is induced at the protein level during ischemia, concomitant with HIF-1alpha induction and a decrease in FGF2 mRNA. In addition, the FGF2 IRES is strongly activated under these ischemic conditions associated with hypoxia, whereas cap-dependent translation is repressed by 4E-BP hypophosphorylation. We also show that up-regulation of FGF2 protein expression in response to hypoxia correlates with the increase of FGF2 IRES activity in vitro, in human retinoblasts 911. The use of siRNAs targeting HIF or FGF2 indicates that FGF2 and HIF-1alpha reciprocally regulate their expression/accumulation, by a negative feedback loop in early hypoxia, followed by a positive feedback loop in late hypoxia. CONCLUSION/SIGNIFICANCE: FGF2 expression is up-regulated in vivo and in vitro in response to hypoxia. Strikingly, this up-regulation is not transcriptional. It seems to occur by an IRES-dependent mechanism, revealing new mechanistic aspects of the hypoxic response. In addition, our data show that FGF2 interacts with HIF-1alpha in a unique crosstalk, with distinct stages in early and late hypoxia. These data reveal the physiological importance of IRES-dependent translation during hypoxic stress and underline the complexity of the cellular response to hypoxia, suggesting a novel role of FGF2 in the regulation of HIF-1alpha during the induction of angiogenesis.

Published
2008
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17. Endothelial DLL4 Is an Adipose Depot–Specific Fasting Sensor Regulating Fatty Acid Fluxes

Author

Alex Aupetit, Pauline Decaunes, Chloé Belles, Elodie Riant, Jean Galitzky, Candice Chapouly, Margaux Laisné, Rémy Flores-Flores, Benoit Chaput, Katell Vié, Jean-François Arnal, Anne Bouloumié, and Anaïs Briot

Subjects
Cardiology and Cardiovascular Medicine
Abstract

Background: Adaptation of fat depots to change in fuel availability is critical for metabolic flexibility and cardiometabolic health. The mechanisms responsible for fat depot-specific lipid sensing and shuttling remain elusive. Adipose tissue microvascular endothelial cells (AT-EC) regulates bidirectional fatty acid fluxes depending on fed or fasted state. How AT-EC sense and adapt to metabolic changes according to AT location remains to be established. Methods: We combined transcriptional analysis of native human AT-EC together with in vitro approaches in primary human AT-EC and in vivo and ex vivo studies of mice under fed and fasted conditions. Results: Transcriptional large-scale analysis of human AT-EC isolated from gluteofemoral and abdominal subcutaneous AT revealed that the endothelium exhibits a fat depot–specific signature associated with lipid handling and Notch signaling enrichment. We uncovered a functional link between metabolic status and endothelial DLL4 (delta-like canonical notch ligand 4), which decreases with fasting. DLL4 regulates fatty acid uptake through nontranscriptional modulation of macropinocytosis-dependent long chain fatty acid uptake. Importantly, the changes in DLL4 expression, in response to energy transition state, is impaired under obesogenic conditions, an early alteration coinciding with a defect in systemic fatty acid fluxes adaptation and a resistance to weight loss. Conclusions: DLL4 is a major actor in the adaptive mechanisms of AT-EC to regulate lipid fluxes. It likely contributes to fat depot-dependent metabolism in response to energy transition states. AT-EC alteration with obesity may favor metabolic inflexibility and the development of cardiometabolic disorders.

Published
2023
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18. Les auteurs

Author

Geneviève, Plu-Bureau, primary, Brigitte, Raccah-Tebeka, additional, Florence,, Trémollières, additional, Vered, Abitbol, additional, Gabriel, André, additional, Jean-François, Arnal, additional, Anne, Bachelot, additional, Clarence, de Belilovsky, additional, Claire, Beylot, additional, Astrid, Blom, additional, Léon, Boubli, additional, Jean-Louis, Bourges, additional, Antoine, Bourret, additional, Gérard, Boutet, additional, Léopoldine, Bricaire, additional, Sophie, Christin-Maitre, additional, Myriam, Dridi Sophie, additional, Caroline, Dubertret, additional, Coralie, Fontaine, additional, Anne, Gompel, additional, Pierre, Gourdy, additional, Virginie, Grouthier, additional, Naima, Hamdaoui, additional, Claude, Hocké, additional, Justine, Hugon-Rodin, additional, Corinne, Lallam, additional, Véronique, Le Guern, additional, Françoise, Lenfant, additional, Brigitte, Letombe, additional, Patrice, Lopes, additional, Sandra, Ly, additional, Anne-Laure,, Madika, additional, Lorraine, Maitrot-Mantelet, additional, Ianis, Marciceau, additional, Pierre, Mares, additional, Virginie, Monnet Corti, additional, Claire, Mounier-Vehier, additional, Emmanuelle, Noirrit-Esclassan, additional, Florence, Pasquier, additional, Olivia, Pietri, additional, Isabelle, Ray-Coquard, additional, Geoffroy, Robin, additional, Christine, Rousset-Jablonski, additional, Sarah, Tebeka, additional, Philippe, Touraine, additional, Blandine, Tramunt, additional, and Marie-Cécile, Valéra, additional

Published
2019
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21. Supplementary Figure 7 from Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis

Author

Françoise Lenfant, Jean-François Arnal, Laurent Brouchet, Pierre Chambon, Andrée Krust, Jean-Michel Foidart, Agnès Noël, Philippe Rochaix, Marie-José Fouque, Marine Adlanmerini, Frédéric Boudou, Silvia Blacher, Isabelle Raymond-Letron, and Christel Péqueux

Abstract

PDF file - 139, ER� is efficiently suppressed in BM and BM-derived cells using chimeric hematopoietic approach

Published
2023
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22. Supplementary Figure 2 from Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis

Author

Françoise Lenfant, Jean-François Arnal, Laurent Brouchet, Pierre Chambon, Andrée Krust, Jean-Michel Foidart, Agnès Noël, Philippe Rochaix, Marie-José Fouque, Marine Adlanmerini, Frédéric Boudou, Silvia Blacher, Isabelle Raymond-Letron, and Christel Péqueux

Abstract

PDF file - 364K, B16K1, LL2 and 4T1 characterization

Published
2023
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23. Supplementary Figure 1 from Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis

Author

Françoise Lenfant, Jean-François Arnal, Laurent Brouchet, Pierre Chambon, Andrée Krust, Jean-Michel Foidart, Agnès Noël, Philippe Rochaix, Marie-José Fouque, Marine Adlanmerini, Frédéric Boudou, Silvia Blacher, Isabelle Raymond-Letron, and Christel Péqueux

Abstract

PDF file - 162K, Vessel diameter quantification by granulometry

Published
2023
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24. Supplementary Figure 3 from Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis

Author

Françoise Lenfant, Jean-François Arnal, Laurent Brouchet, Pierre Chambon, Andrée Krust, Jean-Michel Foidart, Agnès Noël, Philippe Rochaix, Marie-José Fouque, Marine Adlanmerini, Frédéric Boudou, Silvia Blacher, Isabelle Raymond-Letron, and Christel Péqueux

Abstract

PDF file - 122K, B16K1 time- and size-dependent tumor harvesting

Published
2023
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25. Data from Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis

Author

Françoise Lenfant, Jean-François Arnal, Laurent Brouchet, Pierre Chambon, Andrée Krust, Jean-Michel Foidart, Agnès Noël, Philippe Rochaix, Marie-José Fouque, Marine Adlanmerini, Frédéric Boudou, Silvia Blacher, Isabelle Raymond-Letron, and Christel Péqueux

Abstract

Estrogens directly promote the growth of breast cancers that express the estrogen receptor α (ERα). However, the contribution of stromal expression of ERα in the tumor microenvironment to the protumoral effects of estrogen has never been explored. In this study, we evaluated the molecular and cellular mechanisms by which 17β-estradiol (E2) impacts the microenvironment and modulates tumor development of ERα-negative tumors. Using different mouse models of ER-negative cancer cells grafted subcutaneously into syngeneic ovariectomized immunocompetent mice, we found that E2 potentiates tumor growth, increases intratumoral vessel density, and modifies tumor vasculature into a more regularly organized structure, thereby improving vessel stabilization to prevent tumor hypoxia and necrosis. These E2-induced effects were completely abrogated in ERα-deficient mice, showing a critical role of host ERα. Notably, E2 did not accelerate tumor growth when ERα was deficient in Tie2-positive cells, even in mice grafted with wild-type bone marrow. These results were extended by clinical evidence of ERα-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore show that E2 promotes the growth of ERα-negative cancer cells through the activation of stromal ERα (extra-hematopoietic Tie-2 positive cells), which normalizes tumor angiogenesis and allows an adaptation of blood supply to tumors, thereby preventing hypoxia and necrosis. These findings significantly deepen mechanistic insights into the impact of E2 on tumor development with potential consequences for cancer treatment. Cancer Res; 72(12); 3010–9. ©2012 AACR.

Published
2023
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26. Supplementary Figure 6 from Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis

Author

Françoise Lenfant, Jean-François Arnal, Laurent Brouchet, Pierre Chambon, Andrée Krust, Jean-Michel Foidart, Agnès Noël, Philippe Rochaix, Marie-José Fouque, Marine Adlanmerini, Frédéric Boudou, Silvia Blacher, Isabelle Raymond-Letron, and Christel Péqueux

Abstract

PDF file - 204K, B16K1 Tumor necrosis in C57BL/6 mice

Published
2023
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27. Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause

Author

Céline Gérard, Jean-François Arnal, Maud Jost, Jonathan Douxfils, Françoise Lenfant, Coralie Fontaine, René Houtman, David F. Archer, Robert L. Reid, Rogerio A. Lobo, Ulysse Gaspard, Herjan J.T. Coelingh Bennink, Mitchell D. Creinin, and Jean-Michel Foidart

Subjects
Oral, Aging, menopause, Breast Cancer, estrogen, Humans, Pharmacology (medical), Pharmacology & Pharmacy, General Pharmacology, Toxicology and Pharmaceutics, E4, Cancer, Combined, Estetrol, Contraception/Reproduction, Contraceptives, Estrogens, Combined oral contraception, Pharmacology and Pharmaceutical Sciences, General Medicine, estetrol, Contraceptives, Oral, Combined, Contraception, contraception, hemostasis, Female, Patient Safety, venous thrombosis, estrogen receptor
Abstract

Introduction: Estrogens used in women’s healthcare have been associated with increased risks of venous thromboembolism (VTE) and breast cancer. Estetrol (E4), an estrogen produced by the human fetal liver, has recently been approved for the first time as a new estrogenic component of a novel combined oral contraceptive (E4/drospirenone [DRSP]) for over a decade. In phase 3 studies, E4/DRSP showed good contraceptive efficacy, a predictable bleeding pattern, and a favorable safety and tolerability profile. Areas covered: This narrative review discusses E4ʹs pharmacological characteristics, mode of action, and the results of preclinical and clinical studies for contraception, as well as for menopause and oncology. Expert opinion: Extensive studies have elucidated the properties of E4 that underlie its favorable safety profile. While classical estrogens (such as estradiol) exert their actions via both activation of nuclear and membrane estrogen receptor α (ERα), E4 presents a specific profile of ERα activation: E4 binds and activates nuclear ERα but does not induce the activation of membrane ERα signaling pathways in specific tissues. E4 has a small effect on normal breast tissue proliferation and minimally affects hepatic parameters. This distinct profile of ERα activation, uncoupling nuclear and membrane activation, is unique.

Published
2022
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28. A historical view of estrogen effect on arterial endothelial healing: From animal models to medical implication

Author

Coralie Fontaine, Melissa Buscato, Morgane Davezac, Jean-François Arnal, Rana Zahreddine, Natalia F. Smirnova, Marine Adlanmerini, Daniel Henrion, Muriel Laffargue, and Françoise Lenfant

Subjects
Genetically modified mouse, Cell type, Estradiol, Endothelium, business.industry, medicine.drug_class, Estrogen receptor, Estrogens, Atherosclerosis, Cell biology, Endothelial stem cell, Mice, medicine.anatomical_structure, Selective estrogen receptor modulator, Estrogen, Models, Animal, Animals, Medicine, Endothelium, Vascular, Cardiology and Cardiovascular Medicine, business, Receptor
Abstract

Endothelial barrier integrity is required for maintaining vascular homeostasis and fluid balance between the circulation and surrounding tissues. In contrast, abnormalities of endothelial cell function and loss of the integrity of the endothelial monolayer constitute a key step in the onset of atherosclerosis. Endothelial erosion is directly responsible for thrombus formation and cardiovascular events in about one-third of the cases of acute coronary syndromes. Thus, after endothelial injury, the vascular repair process is crucial to restore endothelial junctions and rehabilitate a semipermeable barrier, preventing the development of vascular diseases. Endothelial healing can be modulated by several factors. In particular, 17β-estradiol (E2), the main estrogen, improves endothelial healing, reduces neointimal accumulation of smooth muscle cells and atherosclerosis in several animal models. The aim of this review is to highlight how various experimental models enabled the progress in the cellular and molecular mechanisms underlying the accelerative E2 effect on arterial endothelial healing through the estrogen receptor (ER) α, the main receptor mediating the physiological effects of estrogens. We first summarize the different experimental procedures used to reproduce vascular injury. We then provide an overview of how the combination of transgenic mouse models impacting ERα signalling with pharmacological tools demonstrated the pivotal role of non-genomic actions of ERα in E2-induced endothelial repair. Finally, we describe recent advances in the action of selective estrogen receptor modulators (SERMs) on this beneficial vascular effect, which surprisingly involves different cell types and activates different ERα subfunctions compared to E2.

Published
2021
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29. Loss of function of the maternal membrane oestrogen receptor ERα alters expansion of trophoblast cells and impacts mouse fertility

Author

Mariam Rusidzé, Mélanie C. Faure, Pierre Sicard, Isabelle Raymond-Letron, Frank Giton, Emilie Vessieres, Vincent Prevot, Daniel Henrion, Jean-François Arnal, Charlotte A. Cornil, Françoise Lenfant, Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), GIGA [Université Liège], Université de Liège, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), STROMALab, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Geroscience and rejuvenation research center (RESTORE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Henri Mondor, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), FHU 1,000 Days for Health [Lille], Université de Lille, MORNET, Dominique, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-18-CE14-0016,EstroShear,Rôle du récepteur aux œstrogènes alpha dans la mécanotransduction du flux: conséquences physiopathologiques(2018), CHU Toulouse [Toulouse], and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)

Subjects
Trophoblast cells, Estradiol, Placenta, [SDV]Life Sciences [q-bio], Estrogen Receptor alpha, Parturition, Trophoblasts, Oestrogen receptor ERα (ESR1), [SDV] Life Sciences [q-bio], Mice, Fertility, Membrane signalling, Receptors, Estrogen, Pregnancy, Spiral arterial remodelling, Animals, Humans, Female, Molecular Biology, Progesterone, Developmental Biology
Abstract

The binding of 17β-oestradiol to oestrogen receptor alpha (ERα) plays a crucial role in the control of reproduction, acting through both nuclear and membrane-initiated signalling. To study the physiological role of membrane ERα in the reproductive system, we used the C451A-ERα mouse model with selective loss of function of membrane ERα. Despite C451A-ERα mice being described as sterile, daily weighing and ultrasound imaging revealed that homozygous females do become pregnant, allowing the investigation of the role of ERα during pregnancy for the first time. All neonatal deaths of the mutant offspring mice resulted from delayed parturition associated with failure in pre-term progesterone withdrawal. Moreover, pregnant C451A-ERα females exhibited partial intrauterine embryo arrest at about E9.5. The observed embryonic lethality resulted from altered expansion of Tpbpa-positive spiral artery-associated trophoblast giant cells into the utero-placental unit, which is associated with an imbalance in expression of angiogenic factors. Together, these processes control the trophoblast-mediated spiral arterial remodelling. Hence, loss of membrane ERα within maternal tissues clearly alters the activity of invasive trophoblast cells during placentogenesis. This previously unreported function of membrane ERα could open new avenues towards a better understanding of human pregnancy-associated pathologies.

Published
2022
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31. Early Inactivation of Membrane Estrogen Receptor Alpha (ERα) Recapitulates the Endothelial Dysfunction of Aged Mouse Resistance Arteries

Author

Julie Favre, Emilie Vessieres, Anne-Laure Guihot, Linda Grimaud, Coralyne Proux, Laurent Loufrani, Françoise Lenfant, Coralie Fontaine, Jean-François Arnal, Daniel Henrion, Biomatériaux et Bioingénierie (BB), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and univOAK, Archive ouverte

Subjects
Aging, endothelium, [SDV.BA] Life Sciences [q-bio]/Animal biology, Estradiol, [SDV.BA]Life Sciences [q-bio]/Animal biology, Organic Chemistry, resistance arteries, Estrogen Receptor alpha, General Medicine, estrogen receptors, shear stress, flow-mediated dilation, ageing, Catalysis, Computer Science Applications, Mesenteric Arteries, Inorganic Chemistry, D. Early estrogen receptors, Mice, Animals, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract

Flow-mediated dilation (FMD) of resistance arteries is essential for tissue perfusion but it decreases with ageing. As estrogen receptor alpha (Erα encoded by Esr1), and more precisely membrane ERα, plays an important role in FMD in young mice in a ligand-independent fashion, we evaluated its influence on this arteriolar function in ageing. We first confirmed that in young (6-month-old) mice, FMD of mesenteric resistance arteries was reduced in Esr1−/− (lacking ERα) and C451A-ERα (lacking membrane ERα). In old (24-month-old) mice, FMD was reduced in WT mice compared to young mice, whereas it was not further decreased in Esr1−/− and C451A-ERα mice. Markers of oxidative stress were similarly increased in old WT and C451A-ERα mice. Reduction in oxidative stress with superoxide dismutase plus catalase or Mito-tempo, which reduces mitochondrial superoxide restored FMD to a normal control level in young C451A-ERα mice as well as in old WT mice and old C451A-ERα mice. Estradiol-mediated dilation was absent in old WT mice. We conclude that oxidative stress is a key event in the decline of FMD, and that an early defect in membrane ERα recapitulates phenotypically and functionally ageing of these resistance arteries. The loss of this function could take part in vascular ageing.

Published
2022
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33. Author response: Membrane estrogen receptor alpha (ERα) participates in flow-mediated dilation in a ligand-independent manner

Author

Emilie Vessieres, Julie Favre, Anne-Laure Guihot, Coralyne Proux, Linda Grimaud, Jordan Rivron, Manuela CL Garcia, Léa Réthoré, Rana Zahreddine, Morgane Davezac, Chanaelle Fébrissy, Marine Adlanmerini, Laurent Loufrani, Vincent Procaccio, Jean-Michel Foidart, Gilles Flouriot, Françoise Lenfant, Coralie Fontaine, Jean-François Arnal, and Daniel Henrion

Published
2021
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34. Segregation of nuclear and membrane-initiated actions of estrogen receptor using genetically modified animals and pharmacological tools

Author

Jean-François Arnal, Marine Adlanmerini, Françoise Lenfant, Coralie Fontaine, and Pierre Gourdy

Subjects
Cell Nucleus, Canonical function, Cell Membrane, Estrogen Receptor alpha, Estrogen receptor, SUPERFAMILY, Non genomic signaling, Biology, Biochemistry, Genetically modified organism, Disease Models, Animal, Endocrinology, Nuclear receptor, Protein Domains, Mutation, Animals, Estrogen Receptor beta, Humans, Molecular Biology, Neuroscience, Estrogen receptor alpha, Signal Transduction
Abstract

Estrogen receptor alpha (ERα) and beta (ERβ) are members of the nuclear receptor superfamily, playing widespread functions in reproductive and non-reproductive tissues. Beside the canonical function of ERs as nuclear receptors, in this review, we summarize our current understanding of extra-nuclear, membrane-initiated functions of ERs with a specific focus on ERα. Over the last decade, in vivo evidence has accumulated to demonstrate the physiological relevance of this ERα membrane-initiated-signaling from mouse models to selective pharmacological tools. Finally, we discuss the perspectives and future challenges opened by the integration of extra-nuclear ERα signaling in physiology and pathology of estrogens.

Published
2021

35. Effect of estetrol, a selective nuclear estrogen receptor modulator, in mouse models of arterial and venous thrombosis

Author

Olivier Lairez, Coralie Fontaine, Bernard Payrastre, Jean-François Arnal, Cédric Garcia, Anne Briaux, Cendrine Cabou, Marion Dupuis, Emmanuelle Noirrit-Esclassan, Jean-Michel Foidart, Françoise Lenfant, and Marie-Cécile Valéra

Subjects
Selective Estrogen Receptor Modulators, 0301 basic medicine, medicine.medical_specialty, medicine.drug_class, Estrogen receptor, Hemorrhage, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Internal medicine, Ethinylestradiol, medicine, Animals, Horses, Blood Coagulation, Molecular Biology, Cell Nucleus, Venous Thrombosis, 030219 obstetrics & reproductive medicine, Estradiol, Platelet Count, business.industry, Estetrol, Body Weight, Uterus, Estrogen Receptor alpha, Arteries, Organ Size, medicine.disease, Mice, Inbred C57BL, Menopause, Disease Models, Animal, Venous thrombosis, 030104 developmental biology, chemistry, Estrogen, Hemostasis, Hemorheology, Female, Collagen, business, Ex vivo, medicine.drug
Abstract

Estetrol (E4) is a natural estrogen synthesized exclusively during pregnancy by the human fetal liver, and the physiological role of this hormone is unknown. Interestingly, E4 was recently evaluated in preclinical and phase II-III clinical studies in combination with a progestin, with the advantage to not increase the circulating level of coagulation factors, at variance to oral estradiol or ethinylestradiol. Here, we evaluated the effect of E4 on hemostasis and thrombosis in mouse. Following chronic E4 treatment, mice exhibited a prolonged tail-bleeding time and were protected from arterial and also venous thrombosis in vivo. In addition, E4 treatment decreased ex vivo thrombus growth on collagen under arterial flow conditions. We recently showed that E4 activates uterine epithelial proliferation through nuclear estrogen receptor (ER) α. To analyze the impact of nuclear ERα actions on hemostasis and thrombosis, we generated hematopoietic chimera with bone marrow cells deficient for nuclear ERα. E4-induced protection against thromboembolism was significantly reduced in the absence of hematopoietic nuclear ERα activation, while the increased tail-bleeding time was not impacted by this deletion. In addition to its "liver friendly" profile described in women, our data shows that E4 has anti-thrombotic properties in various mouse models. Altogether, the natural fetal estrogen E4 could represent an attractive alternative to classic estrogens in oral contraception and treatment of menopause.

Published
2018
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36. Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target

Author

Françoise Lenfant, Anne Fougerat, Cheng Zhang, Laurence Gamet-Payrastre, Marion Régnier, Maeva Guillaume, Lorraine Smith, Thierry Levade, Arnaud Polizzi, Yannick Lippi, Caroline Sommer, Marine Huillet, Talal Al Saati, Hervé Guillou, Sandrine Lagarrigue, Sarra Smati, Nicolas Loiseau, Jinghong Wan, Catherine Postic, Yuna Blum, Alain Marrot, Adil Mardinoglu, Tiffany Fougeray, Muhammad Arif, Walter Wahli, Blandine Tramunt, Christophe Bureau, Patricia Dubot, Pierre Gourdy, Sandrine Ellero-Simatos, Céline Lukowicz, Alexandra Montagner, Frédéric Lasserre, Rémy Burcelin, Aurélie Batut, Claire Naylies, Jean-François Arnal, Alexia Laroyenne, Nathalie Hennuyer, Sophie Lotersztajn, Justine Bertrand-Michel, Bart Staels, Jean-Philippe Pradère, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Transcriptomic impact of Xenobiotics (E23 TRiX), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Royal Institute of Technology [Stockholm] (KTH ), ANEXPLO, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Lab Excellence Inflamex (CRI INSERM U1149 - Bichat Medical Faculty), Université Paris Diderot - Paris 7 (UPD7), Plateforme Ezop (Ezop), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage [Rennes] (PEGASE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-INSTITUT AGRO Agrocampus Ouest, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Lee Kong Chian School of Medicine, Nanyang Technological University [Singapour], Université de Lausanne (UNIL), CHU Toulouse [Toulouse], ANR-20-CE14-0035-04, Agence Nationale de la Recherche, FATMAL, Joint Programming Initiative A healthy diet for a healthy life, N/A, Institut National de la Santé et de la Recherche Médicale, N/A, Société Française de Nutrition, N/A, Société Francophone du Diabète, N/A, Société Nationale Française de Gastro-Entérologie, N/A, Association Française pour l'Etude du Foie, N/A, Région Occitanie, N/A, Agreenskills, ANR-17-CE14-0035,PUSHUPS,Etude de la dysfonction des cellules souches musculaires au cours du sepsis(2017), LESUR, Hélène, Etude de la dysfonction des cellules souches musculaires au cours du sepsis - - PUSHUPS2017 - ANR-17-CE14-0035 - AAPG2017 - VALID, Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Ligue Nationale Contre le Cancer (LNCC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Rennes Angers, Université de Lausanne = University of Lausanne (UNIL), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Nanyang Technological University (NTU), Hôpital de Rangueil, Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-ToxAlim (ToxAlim), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD)

Subjects
Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Peroxisome proliferator-activated receptor, Biology, Diet, High-Fat, Transcriptome, Mice, 03 medical and health sciences, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Fibrosis, Internal medicine, lipid metabolism, medicine, Metabolome, Animals, Humans, PPAR alpha, nonalcoholic steatohepatitis, liver metabolism, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Fatty liver, Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Lipid metabolism, Lipidome, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Gene expression profiling, Disease Models, Animal, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, Liver, chemistry, gene expression, Female, 030211 gastroenterology & hepatology, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

ObjectiveWe evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans.DesignDifferent models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver.ResultsThe different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα.ConclusionsThese findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target.Trial registration numberNCT02390232.

Published
2021
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37. Nuclear translocation of MRTFA in MCF7 breast cancer cells shifts ERα nuclear/genomic to extra-nuclear/non genomic actions

Author

Coralie Fontaine, Pascale Le Goff, Michael Primig, Noureddine Boujrad, Gilles Flouriot, Jean-François Arnal, Farzad Pakdel, Charly Jehanno, Denis Michel, Frédéric Percevault, Raphaël Métivier, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University Hospital Basel [Basel], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Chard-Hutchinson, Xavier, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Ligue Nationale Contre Le Cancer, and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Epithelial-Mesenchymal Transition, Estrogen receptor, Breast Neoplasms, 030209 endocrinology & metabolism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Proximity ligation assay, Biochemistry, PI3K, 03 medical and health sciences, P160 family coactivators, 0302 clinical medicine, Endocrinology, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Molecular Biology, Transcription factor, Protein kinase B, SMRT, Nuclear receptor co-repressor 1, src, Cell Nucleus, Binding Sites, Chemistry, Estrogen Receptor alpha, NCOR1, Chromatin, Cell biology, Gene Expression Regulation, Neoplastic, MRTFA, Protein Transport, 030104 developmental biology, Cistrome, MCF-7 Cells, Trans-Activators, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Estrogen receptor alpha, Endocrine resistance
Abstract

International audience; The Myocardin-related transcription factor A [MRTFA, also known as Megakaryoblastic Leukemia 1 (MKL1))] is a major actor in the epithelial to mesenchymal transition (EMT). We have previously shown that activation and nuclear accumulation of MRTFA mediate endocrine resistance of estrogen receptor alpha (ERα) positive breast cancers by initiating a partial transition from luminal to basal-like phenotype and impairing ERα cistrome and transcriptome. In the present study, we deepen our understanding of the mechanism by monitoring functional changes in the receptor’s activity. We demonstrate that MRTFA nuclear accumulation down-regulates the expression of the unliganded (Apo-)ERα and causes a redistribution of the protein localization from its normal nuclear place to the entire cell volume. This phenomenon is accompanied by a shift in Apo-ERα monomer/dimer ratio towards the monomeric state, leading to significant functional consequences on ERα activities. In particular, the association of Apo-ERα with chromatin is drastically decreased, and the remaining ERα binding sites are substantially less enriched in ERE motifs than in control conditions. Monitored by proximity Ligation Assay, ERα interactions with P160 family coactivators are partly impacted when MRTFA accumulates in the nucleus, and those with SMRT and NCOR1 corepressors are abolished. Finally, ERα interactions with kinases such as c-src and PI3K are increased, thereby enhancing MAP Kinase and AKT activities. In conclusion, the activation and nuclear accumulation of MRTFA in ERα positive breast cancer cells remodels both ERα location and functions by shifting its activity from nuclear genome regulation to extra-nuclear non-genomic signaling.

Published
2021
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38. Estetrol prevents western diet-induced obesity and atheroma independently of hepatic estrogen receptor (ER)α

Author

Françoise Lenfant, Rana Zahreddine, Jean-François Arnal, Melissa Buscato, Pierre Gourdy, Cedric Moro, Jean-Michel Foidart, Coralie Fontaine, Marine Adlanmerini, Morgane Davezac, Raphaël Métivier, Marianne Fillet, Gaël Cobraiville, Chard-Hutchinson, Xavier, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Liège, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Agence Nationale de la Recherche, Fondation de France, Fondation pour la Recherche Médicale, Mithra Pharmaceuticals, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Hôpital de Rangueil, and CHU Toulouse [Toulouse]

Subjects
0301 basic medicine, Physiology, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Estrogen receptor, menopause, Mice, chemistry.chemical_compound, 0302 clinical medicine, Mice, Knockout, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Estetrol, Fatty liver, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Lipids, Plaque, Atherosclerotic, 3. Good health, Menopause, [SDV] Life Sciences [q-bio], Adipose Tissue, Liver, Female, estrogen receptor, medicine.medical_specialty, medicine.drug_class, Ovariectomy, 030209 endocrinology & metabolism, metabolic syndrome, 03 medical and health sciences, Physiology (medical), Internal medicine, medicine, Animals, Obesity, fatty liver, business.industry, Cholesterol, Estrogen Receptor alpha, Glucose Tolerance Test, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Receptors, LDL, chemistry, Diet, Western, Estrogen, Hepatocytes, Steatosis, Metabolic syndrome, atherosclerosis, business
Abstract

Estetrol (E4), a natural estrogen synthesized by the human fetal liver, is currently evaluated in phase III clinical studies as a new menopause hormone therapy. Indeed, E4 significantly improves vasomotor and genito-urinary menopausal symptoms and prevents bone demineralization. Compared with other estrogens, E4 was found to have limited effects on coagulation factors in the liver of women allowing to expect less thrombotic events. To fully delineate its clinical potential, the aim of this study was to assess the effect of E4 on metabolic disorders. Here, we studied the pathophysiological consequences of a Western diet (42% kcal fat, 0.2% cholesterol) in ovariectomized female mice under chronic E4 treatment. We showed that E4 reduces body weight gain and improves glucose tolerance in both C57Bl/6 and LDLR-/- mice. To evaluate the role of hepatic estrogen receptor (ER) α in the preventive effect of E4 against obesity and associated disorders such as atherosclerosis and steatosis, mice harboring a hepatocyte-specific ERα deletion (LERKO) were crossed with LDLR-/- mice. Our results demonstrated that, whereas liver ERα is dispensable for the E4 beneficial actions on obesity and atheroma, it is necessary to prevent steatosis in mice. Overall, these findings suggest that E4 could prevent metabolic, hepatic, and vascular disorders occurring at menopause, extending the potential medical interest of this natural estrogen as a new hormonal treatment.NEW & NOTEWORTHY Estetrol prevents obesity, steatosis, and atherosclerosis in mice fed a Western diet. Hepatic ERα is necessary for the prevention of steatosis, but not of obesity and atherosclerosis.

Published
2021
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39. Estrogens and the Angiotensin II Type 2 Receptor Control Flow-Mediated Outward Remodeling in the Female Mouse Mesenteric Artery

Author

Laurent Loufrani, Jordan Rivron, Emilie Vessieres, Daniel Henrion, Jean-François Arnal, Anne-Laure Guihot, Linda Grimaud, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and INSERM U1048 (I2CM)

Subjects
0301 basic medicine, medicine.medical_specialty, Nitric Oxide Synthase Type III, Physiology, Ovariectomy, Vascular Remodeling, 030204 cardiovascular system & hematology, Mechanotransduction, Cellular, Receptor, Angiotensin, Type 2, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, In vivo, Internal medicine, medicine, Animals, Mesenteric arteries, ComputingMilieux_MISCELLANEOUS, TIMP1, Mice, Knockout, CD11b Antigen, Tissue Inhibitor of Metalloproteinase-1, Estradiol, Tumor Necrosis Factor-alpha, Chemistry, Estrogen Replacement Therapy, Blood flow, Mesenteric Arteries, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Gene Expression Regulation, Regional Blood Flow, Ovariectomized rat, Matrix Metalloproteinase 2, Female, Tumor necrosis factor alpha, Stress, Mechanical, Cardiology and Cardiovascular Medicine, Ligation, Artery
Abstract

Flow-mediated outward remodeling (FMR) is involved in postischemic revascularization. Angiotensin II type 2 receptor (AT2R), through activation of T-cell-mediated IL-17 production, and estrogens are involved in FMR. Thus, we investigated the interplay between estrogens and AT2R in FMR using a model of ligation of feed arteries supplying collateral pathways in mouse mesenteric arteries in vivo. Arteries were collected after 2 (inflammatory phase), 4 (diameter expansion phase), and 7 days (remodeling completed). We used AT2R+/+ and AT2R−/− ovariectomized (OVX) female mice treated or not with 17-beta-estradiol (E2). Seven days after ligation, arterial diameter was larger in high flow (HF) compared to normal flow (NF) arteries. FMR was absent in OVX mice and restored by E2. AT2R gene expression was higher in HF than in NF arteries only in E2-treated OVX AT2R+/+ mice. CD11b and TNF alpha levels (inflammatory phase), MMP2 and TIMP1 (extracellular matrix digestion), and NOS3 (diameter expansion phase) expression levels were higher in HF than in NF arteries only in E2-treated AT2R+/+ mice, not in the other groups. Thus, E2 is necessary for AT2R-dependent diameter expansion, possibly through activation of T-cell AT2R, in arteries submitted chronically to high blood flow.

Published
2020
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40. 17β-estradiol promotes acute refeeding in hungry mice via membrane-initiated ERα signaling

Author

Chunmei Wang, Pingwen Xu, Françoise Lenfant, Zhou Pei, Tingting Yang, Ilirjana Hyseni, Hesong Liu, Chen Liang, Xing Cai, Yanlin He, Pierre Gourdy, Yong Xu, Meng Yu, Julia Wang, Yang He, Jean-François Arnal, Kaifan Yu, Hailan Liu, Yongjie Yang, and Na Qu

Subjects
0301 basic medicine, medicine.medical_specialty, lcsh:Internal medicine, medicine.drug_class, Hunger, Ovariectomy, Mutant, Hypothalamus, Estrogen receptor, 030209 endocrinology & metabolism, Endogeny, Hypoglycemia, Biology, medicine.disease_cause, Energy homeostasis, 03 medical and health sciences, Mice, 0302 clinical medicine, E2, Internal medicine, medicine, Animals, Homeostasis, Obesity, lcsh:RC31-1245, Molecular Biology, ERα, Mutation, Estradiol, Feeding, Estrogen Receptor alpha, Cell Biology, Feeding Behavior, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Estrogen, Glucose-sensing, Female, Original Article, Signal Transduction
Abstract

Objective Estrogen protects animals from obesity through estrogen receptor α (ERα), partially by inhibiting overeating in animals fed ad libitum. However, the effects of estrogen on feeding behavior in hungry animals remain unclear. In this study, we examined the roles of 17β-estradiol (E2) and ERα in the regulation of feeding in hungry female animals and explored the underlying mechanisms. Methods Wild-type female mice with surgical depletion of endogenous estrogens were used to examine the effects of E2 supplementation on acute refeeding behavior after starvation. ERα-C451A mutant mice deficient in membrane-bound ERα activity and ERα-AF20 mutant mice lacking ERα transcriptional activity were used to further examine mechanisms underlying acute feeding triggered by either fasting or central glucopenia (induced by intracerebroventricular injections of 2-deoxy-D-glucose). We also used electrophysiology to explore the impact of these ERα mutations on the neural activities of ERα neurons in the hypothalamus. Results In the wild-type female mice, ovariectomy reduced fasting-induced refeeding, which was restored by E2 supplementation. The ERα-C451A mutation, but not the ERα-AF20 mutation, attenuated acute feeding induced by either fasting or central glucopenia. The ERα-C451A mutation consistently impaired the neural responses of hypothalamic ERα neurons to hypoglycemia. Conclusion In addition to previous evidence that estrogen reduces deviations in energy balance by inhibiting eating at a satiated state, our findings demonstrate the unexpected role of E2 that promotes eating in hungry mice, also contributing to the stability of energy homeostasis. This latter effect specifically requires membrane-bound ERα activity., Highlights • Endogenous E2 is required to maintain acute refeeding in hungry female mice after starvation. • Membrane-bound ERα activity in female mice is required for efficient refeeding after starvation. • Membrane-bound ERα activity is required for hypothalamic ERα neurons to respond to hypoglycemia.

Published
2020

41. Estrogen Receptors and Endometriosis

Author

Elodie, Chantalat, Marie-Cécile, Valera, Charlotte, Vaysse, Emmanuelle, Noirrit, Mariam, Rusidze, Ariane, Weyl, Kelig, Vergriete, Etienne, Buscail, Philippe, Lluel, Coralie, Fontaine, Jean-François, Arnal, and Françoise, Lenfant

Subjects
endometriosis, Estrogen Receptor alpha, estrogen receptors, Review, DNA Methylation, Epigenesis, Genetic, lcsh:Chemistry, Endometrium, modulation, Gene Expression Regulation, Receptors, Estrogen, lcsh:Biology (General), lcsh:QD1-999, treatment strategy, Estrogen Receptor beta, Humans, Female, Stromal Cells, lcsh:QH301-705.5
Abstract

Endometriosis is a frequent and chronic inflammatory disease with impacts on reproduction, health and quality of life. This disorder is highly estrogen-dependent and the purpose of hormonal treatments is to decrease the endogenous ovarian production of estrogens. High estrogen production is a consistently observed endocrine feature of endometriosis. mRNA and protein levels of estrogen receptors (ER) are different between a normal healthy endometrium and ectopic/eutopic endometrial lesions: endometriotic stromal cells express extraordinarily higher ERβ and significantly lower ERα levels compared with endometrial stromal cells. Aberrant epigenetic regulation such as DNA methylation in endometriotic cells is associated with the pathogenesis and development of endometriosis. Although there is a large body of data regarding ERs in endometriosis, our understanding of the roles of ERα and ERβ in the pathogenesis of endometriosis remains incomplete. The goal of this review is to provide an overview of the links between endometriosis, ERs and the recent advances of treatment strategies based on ERs modulation. We will also attempt to summarize the current understanding of the molecular and cellular mechanisms of action of ERs and how this could pave the way to new therapeutic strategies.

Published
2020

42. Tamoxifen Accelerates Endothelial Healing by Targeting ERα in Smooth Muscle Cells

Author

Alexia Vinel, Marie-Ange Renault, Françoise Lenfant, Emeline Lhuillier, Adrien Lupieri, Alain-Pierre Gadeau, Natalia F. Smirnova, Melissa Buscato, Morgane Davezac, Coralie Fontaine, Romain Solinhac, Raphaël Métivier, Gilles Flouriot, Emilie Vessieres, Rana Zahreddine, Jean-François Arnal, Daniel Henrion, Muriel Laffargue, Chard-Hutchinson, Xavier, APPEL À PROJETS GÉNÉRIQUE 2018 - Rôle du récepteur aux œstrogènes alpha dans la mécanotransduction du flux: conséquences physiopathologiques - - EstroShear2018 - ANR-18-CE14-0016 - AAPG2018 - VALID, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), The work at INSERM U1048 was supported by INSERM, CHU and Université de Toulouse III, Faculté de Médecine de Toulouse, ANR (EstroShear, ANR-18-CE14-0016-01), Fondation de France, Institut Universitaire de France and Region Occitanie (REGENEV). Work at the CNRS UMR6290 was supported by the CNRS and University of Rennes1., ANR-18-CE14-0016,EstroShear,Rôle du récepteur aux œstrogènes alpha dans la mécanotransduction du flux: conséquences physiopathologiques(2018), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Time Factors, Physiology, [SDV]Life Sciences [q-bio], Estrogen receptor, receptors, endovascular repair, 030204 cardiovascular system & hematology, Muscle, Smooth, Vascular, smooth muscle, 0302 clinical medicine, vascular, estrogen, Medicine, Receptor, skin and connective tissue diseases, Estradiol, tamoxifen, 3. Good health, [SDV] Life Sciences [q-bio], Carotid Arteries, medicine.anatomical_structure, Female, Cardiology and Cardiovascular Medicine, vascular endothelium, hormones, hormone substitutes, and hormone antagonists, Signal Transduction, medicine.drug, Selective Estrogen Receptor Modulators, Endothelium, endothelium, medicine.drug_class, Myocytes, Smooth Muscle, estrogen receptor (ERα), Mice, Transgenic, Article, 03 medical and health sciences, Breast cancer, Animals, smooth muscle cell, Wound Healing, business.industry, Estrogen Receptor alpha, Antagonist, Endothelial Cells, medicine.disease, Mice, Inbred C57BL, Demineralization, Disease Models, Animal, 030104 developmental biology, Estrogen, Tamoxifen and E2 Effects On Reendothelialization Endothelium/Vascular Type/Nitric Oxide Treatment Vascular Biology Estrogen, Cancer research, Carotid Artery Injuries, business, Tamoxifen
Abstract

Rationale: Tamoxifen prevents the recurrence of breast cancer and is also beneficial against bone demineralization and arterial diseases. It acts as an ER (estrogen receptor) α antagonist in ER-positive breast cancers, whereas it mimics the protective action of 17β-estradiol in other tissues such as arteries. However, the mechanisms of these tissue-specific actions remain unclear. Objective: Here, we tested whether tamoxifen is able to accelerate endothelial healing and analyzed the underlying mechanisms. Methods and Results: Using 3 complementary mouse models of carotid artery injury, we demonstrated that both tamoxifen and estradiol accelerated endothelial healing, but only tamoxifen required the presence of the underlying medial smooth muscle cells. Chronic treatment with 17β-estradiol and tamoxifen elicited differential gene expression profiles in the carotid artery. The use of transgenic mouse models targeting either whole ERα in a cell-specific manner or ERα subfunctions (membrane/extranuclear versus genomic/transcriptional) demonstrated that 17β-estradiol-induced acceleration of endothelial healing is mediated by membrane ERα in endothelial cells, while the effect of tamoxifen is mediated by the nuclear actions of ERα in smooth muscle cells. Conclusions: Whereas tamoxifen acts as an antiestrogen and ERα antagonist in breast cancer but also on the membrane ERα of endothelial cells, it accelerates endothelial healing through activation of nuclear ERα in smooth muscle cells, inviting to revisit the mechanisms of action of selective modulation of ERα.

Published
2020
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43. Mutation of Arginine 264 on ERα (Estrogen Receptor Alpha) Selectively Abrogates the Rapid Signaling of Estradiol in the Endothelium Without Altering Fertility

Author

Muriel Le Romancer, Isabelle Raymond-Letron, Anne-Laure Guihot, Chanaelle Fébrissy, Frédéric Boudou, Raphaël Métivier, Melissa Buscato, Coralie Fontaine, Romain Solinhac, Julie Favre, Emilie Vessières, Rana Zahreddine, Claes Ohlsson, Françoise Lenfant, Pierre Gourdy, Marine Adlanmerini, Jean-François Arnal, Pierre Chambon, Typhaine Anquetil, Daniel Henrion, Henrik Laurell, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sahlgrenska Academy at University of Gothenburg [Göteborg], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was also supported by the INSERM, the Université de Toulouse III, the Fondation pour la Recherche Médicale), The Région Midi-Pyrénées and FEDER (Fonds européen de développement régional (REGEN-EVE), the ANR (Agence Nationale de la Recherche, Estroshear, contract # ANR-18-CE14-0016-01), the CNRS, the University of Rennes1. M.A. was supported by grant from the Ministere de la Recherche. C.F was supported by ANR-18-CE14-0016-0, ANR-18-CE14-0016,EstroShear,Rôle du récepteur aux œstrogènes alpha dans la mécanotransduction du flux: conséquences physiopathologiques(2018), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université de Toulouse (UT), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Jonchère, Laurent, APPEL À PROJETS GÉNÉRIQUE 2018 - Rôle du récepteur aux œstrogènes alpha dans la mécanotransduction du flux: conséquences physiopathologiques - - EstroShear2018 - ANR-18-CE14-0016 - AAPG2018 - VALID, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Time Factors, Arginine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], arginine, medicine.disease_cause, 0302 clinical medicine, Re-Epithelialization, Alanine, fertility, 0303 health sciences, Mutation, Chemistry, Estrogen Replacement Therapy, Mesenteric Arteries, [SDV] Life Sciences [q-bio], Vasodilation, medicine.anatomical_structure, Female, Cardiology and Cardiovascular Medicine, Signal Transduction, medicine.medical_specialty, mice, Endothelium, Nitric Oxide Synthase Type III, endothelium, Ovariectomy, Estrous Cycle, Vascular Remodeling, Steroid, 03 medical and health sciences, In vivo, estrogen receptor alpha, Internal medicine, estradiol, medicine, Animals, Point Mutation, 030304 developmental biology, Cell Proliferation, Uterus, Estrogens, Atherosclerosis, Enzyme Activation, Mice, Inbred C57BL, Endocrinology, vascular diseases, Endothelium, Vascular, Carotid Artery Injuries, Estrogen receptor alpha, 030217 neurology & neurosurgery, Cysteine
Abstract

Objective: ERα (estrogen receptor alpha) exerts nuclear genomic actions and also rapid membrane-initiated steroid signaling. The mutation of the cysteine 451 into alanine in vivo has recently revealed the key role of this ERα palmitoylation site on some vasculoprotective actions of 17β-estradiol (E2) and fertility. Here, we studied the in vivo role of the arginine 260 of ERα which has also been described to be involved in its E2-induced rapid signaling with PI-3K (phosphoinositide 3-kinase) as well as G protein in cultured cell lines. Approach and Results: We generated a mouse model harboring a point mutation of the murine counterpart of this arginine into alanine (R264A-ERα). In contrast to the C451A-ERα , the R264A-ERα females are fertile with standard hormonal serum levels and normal control of hypothalamus-pituitary ovarian axis. Although R264A-ERα protein abundance was normal, the well-described membrane ERα–dependent actions of estradiol, such as the rapid dilation of mesenteric arteries and the acceleration of endothelial repair of carotid, were abrogated in R264A-ERα mice. In striking contrast, E2-regulated gene expression was highly preserved in the uterus and the aorta, revealing intact nuclear/genomic actions in response to E2. Consistently, 2 recognized nuclear ERα-dependent actions of E2, namely atheroma prevention and flow-mediated arterial remodeling were totally preserved. Conclusions: These data underline the exquisite role of arginine 264 of ERα for endothelial membrane-initiated steroid signaling effects of E2 but not for nuclear/genomic actions. This provides the first model of fertile mouse with no overt endocrine abnormalities with specific loss-of-function of rapid ERα signaling in vascular functions.

Published
2020
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44. The tissue-specific effects of different 17β-estradiol doses reveal the key sensitizing role of AF1 domain in ERα activity

Author

Frank Giton, Alexia Vinel, Claes Ohlsson, Melissa Buscato, Alain Milon, Sung Hoon Kim, Françoise Lenfant, Pierre Gourdy, Benita S. Katzenellenbogen, Gilles Flouriot, Coralie Fontaine, Isabelle Raymond-Letron, Jean-François Arnal, John A. Katzenellenbogen, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), University of Illinois at Urbana-Champaign [Urbana], University of Illinois System, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut National de la Santé et de la Recherche Médicale, Université de Toulouse, Fondation pour la Recherche Médicale, Agence Nationale de la Recherche, Centre National de la Recherche Scientifique, Ligue Contre le Cancer, NIH R01 DK015556, National Institutes of Health, BCRF 18–082, Breast Cancer Research Foundation, University of Rennes1, Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Chard-Hutchinson, Xavier, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Genetically modified mouse, Gene isoform, Chronic exposure, medicine.medical_specialty, Uterus, 030209 endocrinology & metabolism, Activation function (AF), Biochemistry, Bone and Bones, Structure-Activity Relationship, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Protein Domains, Cell Line, Tumor, Internal medicine, Dose response, medicine, Animals, Tissue specific, Molecular Biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Estradiol, Chemistry, Tissue-specific, Estrogen Receptor alpha, Estrogen receptor alpha (ERα), Transfection, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Mice, Inbred C57BL, Cholesterol, 030104 developmental biology, medicine.anatomical_structure, Organ Specificity, Cell culture, Vagina, Female, Estrogen receptor alpha
Abstract

International audience; 17β-Estradiol (E2) action can be mediated by the full-length estrogen receptor alpha (ERα66), and also by the AF1 domain-deficient ERα (ERα46) isoform, but their respective sensitivity to E2 is essentially unknown. We first performed a dose response study using subcutaneous home-made pellets mimicking either metestrus, proestrus or a pharmacological doses of E2, which resulted in plasma concentrations around 3, 30 and 600 pM, respectively. Analysis of the uterus, vagina and bone after chronic exposure to E2 demonstrated dose-dependent effects, with a maximal response reached at the proestrus-dose in wild type mice expressing mainly ERα66. In contrast, in transgenic mice harbouring only an ERα deleted in AF1, these effects of E2 were either strongly shifted rightward (10-100-fold) and/or attenuated, depending on the tissue studied. Finally, experiments in different cell lines transfected with ERα66 or ERα46 also delineated varying profiles of ERα AF1 sensitivity to E2. Altogether, this work emphasizes the importance of dose in the tissue-specific actions of E2 and demonstrates the key sensitizing role of AF1 in ERα activity.

Published
2020
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46. Estrogen receptor subcellular localization and cardiometabolism

Author

Françoise Lenfant, Maeva Guillaume, Jean-François Arnal, Coralie Fontaine, Pierre Gourdy, Alexandra Montagner, Marine Adlanmerini, and Henrik Laurell

Subjects
0301 basic medicine, lcsh:Internal medicine, medicine.drug_class, Membrane-initiated steroid signals, Active Transport, Cell Nucleus, Estrogen receptor, Review, Estrogen receptors, Genomic effects, Energy balance, Glucose homeostasis, 03 medical and health sciences, medicine, Animals, Humans, Myocytes, Cardiac, lcsh:RC31-1245, Molecular Biology, Transcription factor, Cell Nucleus, Chemistry, Estrogens, Cell Biology, Subcellular localization, Cell biology, Cardiovascular system, 030104 developmental biology, Receptors, Estrogen, Nuclear receptor, Mechanism of action, Estrogen, medicine.symptom, Estrogen receptor alpha, Signal Transduction
Abstract

Background: In addition to their crucial role in reproduction, estrogens are key regulators of energy and glucose homeostasis and they also exert several cardiovascular protective effects. These beneficial actions are mainly mediated by estrogen receptor alpha (ERα), which is widely expressed in metabolic and vascular tissues. As a member of the nuclear receptor superfamily, ERα was primarily considered as a transcription factor that controls gene expression through the activation of its two activation functions (ERαAF-1 and ERαAF-2). However, besides these nuclear actions, a pool of ERα is localized in the vicinity of the plasma membrane, where it mediates rapid signaling effects called membrane-initiated steroid signals (MISS) that have been well described in vitro, especially in endothelial cells. Scope of the review: This review aims to summarize our current knowledge of the mechanisms of nuclear vs membrane ERα activation that contribute to the cardiometabolic protection conferred by estrogens. Indeed, new transgenic mouse models (affecting either DNA binding, activation functions or membrane localization), together with the use of novel pharmacological tools that electively activate membrane ERα effects recently allowed to begin to unravel the different modes of ERα signaling in vivo. Conclusion: Altogether, available data demonstrate the prominent role of ERα nuclear effects, and, more specifically, of ERαAF-2, in the preventive effects of estrogens against obesity, diabetes, and atheroma. However, membrane ERα signaling selectively mediates some of the estrogen endothelial/vascular effects (NO release, reendothelialization) and could also contribute to the regulation of energy balance, insulin sensitivity, and glucose metabolism. Such a dissection of ERα biological functions related to its subcellular localization will help to understand the mechanism of action of “old” ER modulators and to design new ones with an optimized benefit/risk profile. Keywords: Estrogen receptors, Genomic effects, Membrane-initiated steroid signals, Energy balance, Glucose homeostasis, Cardiovascular system

Published
2018
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47. Respective role of membrane and nuclear estrogen receptor (ER) α in the mandible of growing mice: Implications for ERα modulation

Author

Agnès Ostertag, Coralie Fontaine, Marie Cécile Valera, Amélie E. Coudert, Sylvie Babajko, Benita S. Katzenellenbogen, Jean-François Arnal, John A. Katzenellenbogen, Alexia Vinel, Ariane Berdal, and Melissa Buscato

Subjects
0301 basic medicine, Bone mineral, Bone growth, medicine.medical_specialty, medicine.drug_class, Endocrinology, Diabetes and Metabolism, Mandible, Estrogen receptor, Biology, Bone remodeling, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Estrogen, Internal medicine, medicine, Orthopedics and Sports Medicine, Cortical bone, Dental alveolus
Abstract

Estrogens play an important role in bone growth and maturation as well as in the regulation of bone turnover in adults. Although the effects of 17β-estradiol (E2) are well documented in long bones and vertebrae, little is known regarding its action in the mandible. E2 actions could be mediated by estrogen receptor (ER) α or β. ERs act primarily as transcriptional factors through two activation functions (AFs), AF1 and AF2, but they can also elicit membrane-initiated steroid signaling (MISS). The aim of the present study was to define ER pathways involved in E2 effects on mandibular bone. Using mice models targeting ERβ or ERα, we first show that E2 effects on mandibular bone are mediated by ERα and do not require ERβ. Second, we show that nuclear ERαAF2 is absolutely required for all the actions of E2 on mandibular bone. Third, inactivation of ERαMISS partially reduced the E2 response on bone thickness and volume, whereas there was no significant impact on bone mineral density. Altogether, these results show that both nuclear and membrane ERα are requested to mediate full estrogen effects in the mandible of growing mice. Finally, selective activation of ERαMISS is able to exert an effect on alveolar bone but not on the cortical compartment, contrary to its protective action on femoral cortical bone. To conclude, these results highlight similarities but also specificities between effects of estrogen in long bones and in the mandible that could be of interest in therapeutic approaches to treat bone mass reduction. © 2018 American Society for Bone and Mineral Research.

Published
2018
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48. Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications

Author

Raphaël Métivier, Françoise Lenfant, Pierre Gourdy, Coralie Fontaine, Jean-François Arnal, Pierre Chambon, Marine Adlanmerini, John A. Katzenellenbogen, Gilles Flouriot, Daniel Henrion, Benita S. Katzenellenbogen, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular and Integrative Physiology, University of Illinois System, Department of Chemistry, University of Illinois at Urbana-Champaign [Urbana], University of Illinois System-University of Illinois System, Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Selective Estrogen Receptor Modulators, 0301 basic medicine, medicine.medical_specialty, Genotype, Physiology, Transgene, Mice, Transgenic, Biology, 03 medical and health sciences, In vivo, Physiology (medical), Internal medicine, medicine, Animals, Humans, Molecular Biology, Cell Nucleus, [SDV.GEN]Life Sciences [q-bio]/Genetics, Cell Membrane, Estrogen Receptor alpha, Estrogens, General Medicine, Phenotype, In vitro, Cell biology, 030104 developmental biology, Endocrinology, Nuclear receptor, Cell culture, Signal transduction, Estrogen receptor alpha, Signal Transduction
Abstract

International audience; Estrogen receptor alpha (ERα) has been recognized now for several decades as playing a key role in reproduction and exerting functions in numerous nonreproductive tissues. In this review, we attempt to summarize the in vitro studies that are the basis of our current understanding of the mechanisms of action of ERα as a nuclear receptor and the key roles played by its two activation functions (AFs) in its transcriptional activities. We then depict the consequences of the selective inactivation of these AFs in mouse models, focusing on the prominent roles played by ERα in the reproductive tract and in the vascular system. Evidence has accumulated over the two last decades that ERα is also associated with the plasma membrane and activates non-nuclear signaling from this site. These rapid/nongenomic/membrane-initiated steroid signals (MISS) have been characterized in a variety of cell lines, and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS and the generation of mice expressing an ERα protein impeded for membrane localization have begun to unravel the physiological role of MISS in vivo. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators based on the integration of the physiological and pathophysiological roles of MISS actions of estrogens.

Published
2017
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49. Hormones endogènes et exogènes

Author

Jean-François Arnal, Theodora Bejan-Angoulvant, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de Rangueil, CHU Toulouse [Toulouse], CCSD, Accord Elsevier, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), GICC EA 7501, PATCH (Pharmacologie des anticorps thérapeutiques chez l'Homme) (PATCH), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT)-Université de Tours (UT), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC)

Subjects
Drug, medicine.medical_specialty, 030219 obstetrics & reproductive medicine, business.industry, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Endogeny, General Medicine, 030204 cardiovascular system & hematology, medicine.disease, 3. Good health, Vasoprotective, [SDV] Life Sciences [q-bio], Menopause, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Synthetic Progestins, Internal medicine, medicine, Estrogen replacement therapy, business, hormones, hormone substitutes, and hormone antagonists, media_common
Abstract

International audience; Before menopause, women are protected from the risk of hypertension and atherosclerosis by endogenous estrogens. Estrogens have a vasoprotective role, while progesterone seems to have a neutral effect. Exogenous estrogens used in menopausal treatment have vascular effects. These effects depend of type, dose and administration type, and with age and atherosclerosis stages. Synthetic progestins have varying clinical effects. Each drug must be evaluated separately.

Published
2019
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