Estrogen inhibits the vascular injury response in estrogen receptor β-deficient female mice

Karas, Richard H.; Hodgin, Jeffrey B.; Kwoun, Moon; Krege, John H.; Aronovitz, Mark; Mackey, William C.; Gustafsson, Jan Åke; Korach, Kenneth S.; Smithies, Oliver; Mendelsohn, Michael E.

doi:10.1073/pnas.96.26.15133

Cited by 240 publications

(139 citation statements)

References 45 publications

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“…Estrogen continues to provide protection against vascular injury in mice in which ER␣ has been disrupted (71), and the expression of ER␤, but not ER␣, is elevated after vascular injury in male rats (72). Estrogen also provides protection against vascular injury in mice in which ER␤ has been disrupted (73), suggesting the possibility that either of the two known estrogen receptors is sufficient to protect against vascular injury or that some other unknown signaling pathway is involved.…”

Section: Discussionmentioning

confidence: 98%

Estrogen Induces the Akt-dependent Activation of Endothelial Nitric-oxide Synthase in Vascular Endothelial Cells

Hisamoto¹,

Ohmichi²,

Kurachi³

et al. 2001

Journal of Biological Chemistry

353

250

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Although estrogen is known to activate endothelial nitric oxide synthase (eNOS) in the vascular endothelium, the molecular mechanism responsible for this effect remains to be elucidated. In studies of both human umbilical vein endothelial cells ( The inhibitory effect of estrogen on the development of atherosclerosis has been suggested by abundant human epidemiological and animal experimental data (1-9). The incidence of atherosclerotic diseases is lower in premenopausal women than in men, steeply rises in postmenopausal women, and is reduced to premenopausal levels in postmenopausal women who receive estrogen therapy (10 -12). Until recently, the atheroprotective effects of estrogen were attributed principally to the effects on serum lipid concentrations. However, estrogeninduced alterations in serum lipids account for only approximately one-third of the observed clinical benefits of estrogen (12)(13)(14). Recent evidence suggests that the direct actions of estrogen on blood vessels contribute to the cardioprotective effects of estrogen (13, 15). There are many kinds of direct effects of estrogen on blood vessels, such as estrogen-induced increases of vasodilatation and inhibition of the response of blood vessels to injury and the development of atherosclerosis. However, the molecular mechanism underlying the estrogeninduced vasodilatation has not yet been determined. Several studies suggest that a key mediator of this vasodilator response could be the endothelium-derived relaxing factor nitric oxide (NO), and that brief treatment with estrogen increases basal NO release in endothelial cells without elevation of eNOS mRNA or protein (16). Estrogen activates endothelial nitric oxide synthase (eNOS) without altering expression of the eNOS gene in vascular endothelium (17)(18)(19)(20). However, the details of the mechanism of the estrogen-induced eNOS activation are not yet well understood.The serine/threonine kinase termed Akt or protein kinase B (PKB) 1 is an important regulator of various cellular processes, including glucose metabolism and cell survival (21, 22). Activation of receptor tyrosine kinases and G-protein-coupled receptors, and stimulation of cells by mechanical force, can lead to the phosphorylation and activation of . Akt was identified as a downstream component of survival signaling through phosphatidylinositol 3-kinase (PI3K) (26 -30). Akt may be regulated by both phosphorylation and the direct binding of PI3K lipid products to the Akt pleckstrin homology domain. Akt can then phosphorylate substrates such as glycogen synthase kinase-3, 6-phosphofructo-2-kinase, and BAD. More recently, it was found that eNOS is also an Akt substrate and is activated by Akt-dependent phosphorylation to release NO in endothelial cells (31-34).The actions of estrogen can be mediated by the classical nuclear receptors, ER␣ and ER␤ (35,36) or through other putative membrane receptors. By definition, rapid effects of estrogen that involve nongenomic mechanisms are independent of transcriptional activation by the nuclea...

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Section: Discussionmentioning

confidence: 98%

Estrogen Induces the Akt-dependent Activation of Endothelial Nitric-oxide Synthase in Vascular Endothelial Cells

Hisamoto¹,

Ohmichi²,

Kurachi³

et al. 2001

Journal of Biological Chemistry

353

250

View full text Add to dashboard Cite

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“…Also, the original ER␣ gene-deleted mouse (ER␣KO Chapel Hill), targeted for deletion within exon 1, was reexamined after vascular responses were found to be maintained. Indeed, truncation variants resulting from both splice and internal translation initiation sites within exon 2, ER55 and ER46, were demonstrated in the vasculature of that mouse and were capable of mediating estrogen responses (24,33,34).…”

Section: Vehicle) (C and D)mentioning

confidence: 99%

Variant estrogen receptor–c-Src molecular interdependence and c-Src structural requirements for endothelial NO synthase activation

Hisamoto²,

Kim³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…The importance of estradiol metabolites in vasoprotection is further supported by findings that in obese ZSF1 rats that exhibit the metabolic syndrome, treatment with 2-hydroxyestradiol, the precursor of 2-methoxyestradiol, decreases body weight, improves vascular endothelial function, decreases nephropathy, exerts antidiabetic actions, and lowers blood pressure and blood cholesterol. 65 Estradiol prevents neointima formation in mice lacking functional ER␣ and ER␤, 66,67 suggesting that the protective effects of estradiol on the cardiovascular system may be ER-independent. Estradiol prevents neointima formation in gonadectomized, but not intact, male rats, 68 even though male rats express ERs.…”

Section: Type Of Estrogenmentioning

confidence: 99%

Hormone Replacement Therapy and Cardiovascular Disease

et al. 2004

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Abstract-Observational studies in humans and experimental studies in animals and isolated cells supported the widely held belief that hormone replacement therapy protects the cardiovascular system from disease. To nearly everyone's astonishment, the Women's Health Initiative Study and the Heart and Estrogen/Progestin Replacement Study overturned the conclusion that hormone replacement therapy protects the cardiovascular system and, in fact, supported the opposite view that such therapy may actually increase the risk of cardiovascular disease. Observational Studies Suggest HRT Has Beneficial Cardiovascular EffectsIn modern societies, cardiovascular disease is the main cause of morbidity and mortality in men and women. Women, however, are comparatively spared. For example, in people younger than age 65 years, the prevalence of coronary heart disease (CHD) is several-fold higher in men. 3,4 Although CHD prevalence increases with age in both genders, before the age of 65 years the relationship between age and CHD prevalence is shifted rightward by 5 years in women; 5,6 compared with postmenopausal women, CHD deaths are rare in premenopausal women. 7 Autopsy studies demonstrated increased CHD in oophorectomized young women, 8 and several studies demonstrated an increased risk of cardiovascular disease in women with bilateral oophorectomy without HRT compared with those receiving HRT. 9,10 Women with natural early-onset menopause who did not use HRT had a greater likelihood for CHD compared with age-matched premenopausal women. 9,11 Also, studies reported an inverse relationship between age at natural menopause and mortality from CHD 12,13 and carotid atherosclerosis. 14 Bush et al demonstrated that HRT was associated with reduced all-cause mortality in postmenopausal women, 15 primarily because of favorable effects on high-density lipoprotein. 16 Barrett-Connor and Bush 8 reported that many, but not all, cross-sectional and prospective studies demonstrated a statistically significant reduction in CHD in women taking HRT, and Grady et al 17 presented a meta-analysis of published observational studies and reported that HRT was associated with one-third less fatal CHD. An up-to-date meta-analysis of 25 observational studies conducted between 1976 and 1996 showed that the relative risk for CHD in women who ever used HRT compared with never users was 0.70. 18 The Nurses' Health Study was a comprehensive investigation conducted in 121 700 female nurses aged 30 to 55 years. In the latest report, compiled with data from 70 533 postmenopausal women followed-up for 20 years, the overall risk of CHD in current users of HRT was reduced, with a relative risk of 0.61 after adjustment for age and cardiovascular risk factors. 19

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Estrogen inhibits the vascular injury response in estrogen receptor β-deficient female mice

Cited by 240 publications

References 45 publications

Estrogen Induces the Akt-dependent Activation of Endothelial Nitric-oxide Synthase in Vascular Endothelial Cells

Estrogen Induces the Akt-dependent Activation of Endothelial Nitric-oxide Synthase in Vascular Endothelial Cells

Variant estrogen receptor–c-Src molecular interdependence and c-Src structural requirements for endothelial NO synthase activation

Hormone Replacement Therapy and Cardiovascular Disease

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