Modified LDL–Mediated Increases in Endothelial Layer Permeability Are Attenuated With 17β-Estradiol

Gardner, G.; Banka, Carole L.; Roberts, Kim A.; Mullick, Adam E.; Rutledge, John C.

doi:10.1161/01.atv.19.4.854

Cited by 39 publications

(23 citation statements)

References 53 publications

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“…E 2 , 2-ME, and isoflavones enhance endothelial barrier function and reduce its permeability to pro-atherogenic factors such as native and oxidized LDLs (Carbajal & Schaeffer 1998, Delarue et al 1998, Fujimoto et al 1998, Gardner et al 1999, Chi et al 2004, Liu et al 2005, Sumanasekera et al 2007, Dubey & Jackson 2009). The latter effect depends on the modulation of tight junction proteins such as occludin and/or claudin and is mediated via both ERa and ERb (Ye et al 2003, Burek et al 2010, Sandoval & Witt 2011.…”

Section: Mechanisms Underlying Anti-atherogenic Effects Of Estrogens mentioning

confidence: 99%

Estrogens and atherosclerosis: insights from animal models and cell systems

Nofer

2012

Journal of Molecular Endocrinology

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Estrogens not only play a pivotal role in sexual development but are also involved in several physiological processes in various tissues including vasculature. While several epidemiological studies documented an inverse relationship between plasma estrogen levels and the incidence of cardiovascular disease and related it to the inhibition of atherosclerosis, an interventional trial showed an increase in cardiovascular events among postmenopausal women on estrogen treatment. The development of atherosclerotic lesions involves complex interplay between various pro-or anti-atherogenic processes that can be effectively studied only in vivo in appropriate animal models. With the advent of genetic engineering, transgenic mouse models of atherosclerosis have supplemented classical dietary cholesterolinduced disease models such as the cholesterol-fed rabbit. In the last two decades, these models were widely applied along with in vitro cell systems to specifically investigate the influence of estrogens on the development of early and advanced atherosclerotic lesions. The present review summarizes the results of these studies and assesses their contribution toward better understanding of molecular mechanisms underlying anti-and/or pro-atherogenic effects of estrogens in humans.

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Section: Mechanisms Underlying Anti-atherogenic Effects Of Estrogens mentioning

confidence: 99%

Estrogens and atherosclerosis: insights from animal models and cell systems

Nofer

2012

Journal of Molecular Endocrinology

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“…36 We confirmed that E2 treatment resulted in a significant decrease in endothelial expression of vascular cell adhesion molecule-1 at the aortic sinus in hypercholesterolemic mice. 37 Whether the atheroprotective effect of E2 involves the inhibition of transendothelial atherogenic lipoprotein accumulation 38 or inflammatory cell trafficking at lesion-prone sites, 17 prevention of endothelial cell death, 39 or stimulation of endothelial healing 8,21 remains to be investigated in future studies.…”

Section: Billon-galés Et Al Endothelial Er␣ and Atheroprotection By Ementioning

confidence: 99%

Endothelial Estrogen Receptor-α Plays a Crucial Role in the Atheroprotective Action of 17β-Estradiol in Low-Density Lipoprotein Receptor–Deficient Mice

et al. 2009

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Background-The prevention of early atheroma by estrogens has been clearly demonstrated in all animal models and appears to be mediated through a direct action on the arterial wall rather than through an effect on the lipoprotein profile.The goal of the present study was to evaluate which cellular target is crucial in this beneficial action of estradiol. Methods and Results-We first confirmed the key role of estrogen receptor-␣ (ER␣) in the atheroprotective effect of estradiol, because this action was completely abolished in mice deficient in both the low-density lipoprotein receptor (LDLr) and ER␣. Second, using chimeric mice with an ER␣ deficiency in the hematopoietic lineage, we showed the persistence of the protective action of estradiol, which suggests the involvement of extrahematopoietic ER␣. Third, we showed that loxP-flanked ER␣ mice (ER␣ flox/flox ) bred with Tie2-Cre ϩ mice on an LDLr Ϫ/Ϫ background had complete inactivation of ER␣ in most hematopoietic and all endothelial cells. Remarkably, in this mouse model, the atheroprotective effect of estradiol was completely abolished. Fourth, the atheroprotective effect of estradiol remained abolished in Tie2-Cre ϩ ER␣ flox/flox LDLr Ϫ/Ϫ mice transplanted with either Tie2-Cre ϩ ER␣ flox/flox or ER␣ Ϫ/Ϫ bone marrow, whereas it was present in analogous chimeric Tie2-Cre Ϫ ER␣ flox/flox LDLr Ϫ/Ϫ receivers expressing endothelial ER␣. Conclusions-We demonstrate directly and for the first time that endothelial ER␣ represents a key target of the atheroprotective effect of estradiol, whereas hematopoietic ER␣ is dispensable. Selective estrogen receptor modulators that mimic the endothelial action of estradiol should now be considered in atheroprotection. Key Words: atherosclerosis Ⅲ endothelium Ⅲ estrogens Ⅲ hormones Ⅲ receptors E pidemiological studies have shown that women are protected against coronary heart diseases (CHDs) before menopause, which suggests a beneficial action of endogenous estrogens. This vasculoprotective action of estrogens has been demonstrated clearly in animal models of early atheroma, because 17␤-estradiol (E2) has been shown to strongly prevent fatty streak deposition in monkeys, rabbits, and mice (apolipoprotein E-deficient [ApoE Ϫ/Ϫ ] and low-density lipoprotein receptor-deficient [LDLr Ϫ/Ϫ mice]; for references, see Arnal et al 1 ). Although the main randomized controlled trial (the Women's Health Initiative) did not confirm the preventive action of estrogens against CHD, women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk seen among women more distant from menopause. 2,3 Interestingly, the importance of age in the action of estrogens on endothelial function, a surrogate end point and pathophysiological mechanism, was suggested as early as 2001. 4 Clinical Perspective on p 2576Animal models nicely mimic this discrepancy, and primate studies revealed that the efficacy of estrogens on plaque progression was inversely related to the duration of the estrogen-depri...

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“…Estradiol, which is a phenol with anti-oxidant properties, prevents the oxidation of LDL and VLDL to oxLDL and oxVLDL, and protects the vasculature against the deleterious effects of ox-lipids [14]. Estradiol prevents compromise of the endothelial barrier mediated by mmLDL and attenuates accumulation of mmLDL and oxLDL in the artery wall [94]. TNF-a-mediated oxidation and accumulation of LDL in the artery wall is prevented by estradiol [95].…”

Section: Role Of Interactions With Lipoproteinsmentioning

confidence: 99%

Vascular consequences of menopause and hormone therapy: Importance of timing of treatment and type of estrogen

Dubey

Imthurn

Barton

et al. 2005

Cardiovascular Research

212

170

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Premenopausal women have a lower risk for cardiovascular events, and mortality due to coronary vascular disease (CVD) in premenopausal women is rare. These facts suggest that endogenous estrogens, such as estradiol, protect the cardiovascular system, and several observational studies and a few small clinical studies conducted in healthy and younger postmenopausal women support this hypothesis. In contrast, two large randomized clinical trials (RCTs), using conjugated equine estrogens and conducted in older women with established CVD or without overt CVD, failed to demonstrate protection against CVD by exogenous estrogens. These divergent findings have resulted in confusion with regard to the association between estrogen deficiency and CVD in postmenopausal women. In order to reconcile these contradictory findings, it is necessary to examine the pathophysiology associated with age-dependent changes within the vessel wall and to compare the pharmacology of different types of estrogens. Understanding age-dependent changes in vascular pathology and the pharmacology of different estrogens may facilitate the development of therapeutic strategies for hormone replacement therapy (HRT) that would be effective in delaying vascular remodeling leading to CVD following menopause. In this review we provide an overview of the impact of menopause and estrogen deficiency on vascular remodeling and emphasize the importance of timing and type of estrogen to achieve maximum benefits with regard to reducing the risk of CVD.

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Modified LDL–Mediated Increases in Endothelial Layer Permeability Are Attenuated With 17β-Estradiol

Cited by 39 publications

References 53 publications

Estrogens and atherosclerosis: insights from animal models and cell systems

Estrogens and atherosclerosis: insights from animal models and cell systems

Endothelial Estrogen Receptor-α Plays a Crucial Role in the Atheroprotective Action of 17β-Estradiol in Low-Density Lipoprotein Receptor–Deficient Mice

Vascular consequences of menopause and hormone therapy: Importance of timing of treatment and type of estrogen

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