Endothelial Estrogen Receptor α Plays an Essential Role in the Coronary and Myocardial Protective Effects of Estradiol in Ischemia/Reperfusion

Favre, Julie; Gao, Ji; Henry, Jean‐Paul; Rémy-Jouet, Isabelle; Fourquaux, Isabelle; Billon-Galès, Audrey; Thuillez, Christian; Arnal, Jean‐François; Lenfant, Françoise; Richard, Vincent

doi:10.1161/atvbaha.110.213637

Cited by 62 publications

(34 citation statements)

References 37 publications

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“…This finding conforms with the key role of ERα in other beneficial effects of E2, such as acceleration of reendothelialization, 34 prevention of atheroma, 35 promotion of skin flap revascularization, 17 and protection against myocardial ischemia/reperfusion. 36 To identify which step was influenced by ERα activation in the pathway involved in shear stress-mediated remodeling, we isolated arteries 2 and 4 days after ligation. To cause diameter enlargement, flow (shear stress) first induces inflammation and macrophage infiltration (day 1 to day 2), 13 followed by a rise in oxidative stress 14 that favors the formation of peroxinitrite (ONOO − ), which in turn activates MMPs and extracellular matrix digestion between days 3 and 4.…”

Section: Discussionmentioning

confidence: 99%

Key Role of Estrogens and Endothelial Estrogen Receptor α in Blood Flow–Mediated Remodeling of Resistance Arteries

Tarhouni

Guihot

Freidja

et al. 2013

ATVB

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Objective-Flow-(shear stress-)mediated outward remodeling of resistance arteries is involved in collateral growth during postischemic revascularization. As this remodeling is especially important during pregnancy, we hypothesized that estrogens may be involved. A surgical model eliciting a local increase in blood flow in 1 mesenteric resistance artery was used in 3-month-old ovariectomized female rats either treated with 17-β-estradiol (E2) or left untreated. Methods and Results-After 14 days, arterial diameter was greater in high-flow arteries than in normal-flow vessels. An ovariectomy suppressed high-flow remodeling, while E2 restored it. High-flow remodeling was absent in mice lacking the estrogen receptor α but not estrogen receptor β. The kinetics of inflammatory marker expression, macrophage infiltration, oxidative stress, and metaloproteinases expression were not altered by the absence of E2 after 2 and 4 days, that is, during remodeling. Nevertheless, E2 was required for the increase in endothelial nitric oxide synthase expression and activation at day 4 when diameter expansion occurs. Finally, the impact of E2 on the endothelium appeared crucial for high-flow remodeling, as this E2 action was abrogated in mice lacking endothelial NOS, as well as in Tie2-Cre(+) ERα f/f mice. Conclusion-We

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Section: Discussionmentioning

confidence: 99%

Key Role of Estrogens and Endothelial Estrogen Receptor α in Blood Flow–Mediated Remodeling of Resistance Arteries

Tarhouni

Guihot

Freidja

et al. 2013

ATVB

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“…Selectively, knocking out ER α reduces estrogen’s protection by increasing atherosclerotic plaques and serum cholesterol levels in ApoE mice (reviewed in Mendelsohn 2000; Rossouw et al 2007). Loss of ER α specifically in coronary endothelial cells abolishes the protective action of estrogen to limit infarct size and coronary endothelial function (Favre et al 2010). The loss of endothelial ER α suggests a critical role for ER α in the estrogen-induced prevention of endothelial dysfunction after ischemia/reperfusion.…”

Section: Cardiovascular Disease and Ermentioning

confidence: 99%

Estrogen receptors and human disease: an update

2012

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A myriad of physiological processes in mammals are influenced by estrogens and the estrogen receptors (ERs), ERα and ERβ. As we reviewed previously, given the widespread role for estrogen in normal human physiology, it is not surprising that estrogen is implicated in the development or progression of a number of diseases. In this review, we are giving a 5-year update of the literature regarding the influence of estrogens on a number of human cancers (breast, ovarian, colorectal, prostate, and endometrial), endometriosis, fibroids, and cardiovascular disease. A large number of sophisticated experimental studies have provided insights into human disease, but for this review, the literature citations were limited to articles published after our previous review (Deroo and Korach in J Clin Invest 116(3):561–570, 2006) and will focus in most cases on human data and clinical trials. We will describe the influence in which estrogen’s action, through one of or both of the ERs, mediates the aforementioned human disease states.

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“…Platelets were prepared as previously described, 27 then examined using a transmission electron microscope at an accelerating voltage of 5 kV.…”

Section: Electron Microscopymentioning

confidence: 99%

Chronic estradiol treatment reduces platelet responses and protects mice from thromboembolism through the hematopoietic estrogen receptor α

Valera

Gratacap

Gourdy

et al. 2012

Blood

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Although estrogens are known to have a deleterious effect on the venous thrombosis risk and a preventive action on the development of arterial atheroma, their effect on platelet function in vivo remains unclear. Here, we demonstrate that a chronic high physiologic level of estradiol (E2) in mice leads to a marked decrease in platelet responsiveness ex vivo and in vivo compared with ovariectomized controls. E2 treatment led to increased bleeding time and a resistance to thromboembolism. Hematopoietic chimera mice harboring a selective deletion of estrogen receptors (ERs) ␣ or ␤ were used to demonstrate that the effects of E2 were exclusively because of hematopoietic ER␣. Within ER␣ the activation function-1 domain was not required for resistance to thromboembolism, as was previously shown for atheroprotection. This domain is mandatory for E2-mediated reproductive function and suggests that this role is controlled independently. Differential proteomics indicated that E2 treatment modulated the expression of platelet proteins including ␤1 tubulin and a few other proteins that may impact platelet production and activation. Overall, these data demonstrate a previously unrecognized role for E2 in regulating the platelet proteome and platelet function, and point to new potential antithrombotic and vasculoprotective therapeutic strategies. (Blood. 2012;120(8):1703-1712) IntroductionEstradiol-17␤ (E2) and estrogen receptors (ERs) are well known for their pivotal role in sexual development and reproduction. However, they can also modulate cardiovascular and metabolic risk, autoimmune disease progression, and cancer growth. These pleiotropic effects are a consequence of both the widespread expression of ER in many cell populations within the body as well as possibly reflecting the ancestral status of ER in the steroid receptor family. 1 Epidemiologic and experimental studies now support an atheroprotective effect of both endogenous and exogenous estrogens. The Women's Health Initiative study did not show a coronary protective effect of estrogen in postmenopausal women, 2 but subsequent studies have shown that this was because of both inappropriate timing (ie, administering the hormone therapy too late) and the identity of the associated progestin. 3,4 The route of administration of estrogens (oral versus transdermal) has also been shown to have a major impact on the risk of venous thromboembolism. 5 Together these studies indicate that the beneficial or deleterious action of estrogens are strongly influenced by the dose, route, and timing of the hormonal treatment alongside age, genetic, and environmental factors.Although the impact of estrogens on coagulation and venous thromboembolism risk has received much attention, their effect on platelet function remains poorly characterized in vivo. After estrogen treatment, one study reported reduced platelet activation 6 whereas 2 others found increased activation. 7,8 Platelet activation markers were also found at higher levels in postmenopausal compared with premenopausal women...

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Endothelial Estrogen Receptor α Plays an Essential Role in the Coronary and Myocardial Protective Effects of Estradiol in Ischemia/Reperfusion

Cited by 62 publications

References 37 publications

Key Role of Estrogens and Endothelial Estrogen Receptor α in Blood Flow–Mediated Remodeling of Resistance Arteries

Key Role of Estrogens and Endothelial Estrogen Receptor α in Blood Flow–Mediated Remodeling of Resistance Arteries

Estrogen receptors and human disease: an update

Chronic estradiol treatment reduces platelet responses and protects mice from thromboembolism through the hematopoietic estrogen receptor α

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