Abnormal Vascular Function and Hypertension in Mice Deficient in Estrogen Receptor β

Zhu, Yan; Bian, Zhaolian; Lu, Ping; Karas, Richard H.; Bao, Lingzhi; Cox, Daniel H.; Hodgin, Jeffrey B.; Shaul, Philip W.; Thorén, Peter; Smithies, Oliver; Gustafsson, Jan Åke; Mendelsohn, Michael E.

doi:10.1126/science.1065250

Cited by 453 publications

(347 citation statements)

References 25 publications

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“…There was no trend with time over the 1-h period, suggesting that the animals measurements were stable (F between times Ͻ 0.3). The values of MAP and HR are very similar to those measured by telemetry in conscious female WT mice at the same time of day by Zhu and colleagues (22). The maximum rate of change in BP (dP/dT) that occurs during the systole was 40% greater in the ArKO mice compared with WT (1427 Ϯ 9 compared with 1019 Ϯ 14 mm Hg/sec; P Ͻ 0.05; Fig.…”

Section: Cardiovascular Measurementssupporting

confidence: 83%

“…Whether this change could explain the lower diastolic BP is debatable, because the majority of effects of estrogen suggest that it has a mainly vasodilatory role on the vasculature. The estrogen receptor ␤-deficient mice develop sustained systolic and diastolic hypertension, but only as they age (Ͼ6 months) (22). Estrogen reverses acetylcholineinduced vasoconstriction of coronary vessels, possibly via facilitation of endothelium-dependent relaxation (23), which may be mediated by an enhancement of NO production via stimulation of NO synthase (24).…”

Section: Discussionmentioning

confidence: 99%

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Aromatase-Deficient (ArKO) Mice Have Reduced Blood Pressure and Baroreflex Sensitivity

Head

Obeyesekere

Jones³

et al. 2004

Endocrinology

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Aromatase-deficient (ArKO) mice are deficient in estrogens due to deletion of the aromatase gene. We hypothesized that there may be changes in the cardiovascular system of ArKO mice because of evidence linking estrogens with improved cardiovascular outcomes and the induction of the glucocorticoid-metabolizing enzyme, 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2), gene in the kidney, which is important for the regulation of blood pressure (BP). BP and baroreflex sensitivity (BRS) in female conscious ArKO mice were compared with those in age-and weight-matched wild-type (WT) mice. Power spectral analysis was used to determine cardiovascular variability and BRS. Although systolic BP was similar in the two groups, diastolic and mean BPs were lower in the ArKO mice (؊6.3 ؎ 1.9 and ؊4.6 ؎ 2.1 mm Hg, respectively).Heart rate (HR) was greater in the ArKO mice (؉36 ؎ 6 beats/ min). The mean BP in WT mice was 105 mm Hg, and the HR was 481 beats/min. In the autonomic frequency range, BP variability was 74% greater, and HR variability was only 26% that in WT mice. The BRS of ArKO mice was 46% of the value observed in WT mice. 11␤HSD2 levels were unaltered in ArKO mice, except in the kidney, where they were only 10% of WT levels. Estradiol administration to ArKO mice restored renal 11␤HSD2 to WT levels. The results show that ArKO mice have lower diastolic BP, but increased BP variability, perhaps due to an impaired BRS. Thus, aromatase activity is critical for normal autonomic control of the heart and, hence, for reducing the deleterious effects of high BP variability. (Endocrinology 145: 4286 -4291, 2004)

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Section: Cardiovascular Measurementssupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Aromatase-Deficient (ArKO) Mice Have Reduced Blood Pressure and Baroreflex Sensitivity

Head

Obeyesekere

Jones³

et al. 2004

Endocrinology

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“…In addition, estrogen deficiency did not cause a rise in the blood pressure of this sclerosis-prone mouse model as it had been recently described in mice, which lack ER␤ expression. 19 Although both intact and Ovx ROP Os/ϩ mice developed glomerular hypertrophy and glomerulosclerosis, these abnormalities were more pronounced and severe in the Ovx animals. This was associated with a marked distortion of the glomerular architecture because of basement membrane collapse as well as segmental effacement of the podocyte processes in the Ovx mice.…”

Section: Discussionmentioning

confidence: 96%

Estrogen Deficiency Accelerates Progression of Glomerulosclerosis in Susceptible Mice

Elliot¹,

Karl²,

Berho³

et al. 2003

The American Journal of Pathology

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Estrogen deficiency may contribute to the development and progression of glomerulosclerosis in postmenopausal women. The responsiveness to estrogens could be controlled by genetic traits related to those that determine the susceptibility to glomerular scarring. This study was undertaken to determine whether the intensity of the sclerotic response was modified by the estrogen status in sclerosis-prone ROP Os/؉ mice. Ovariectomized ROP Os/؉ mice developed more severe renal dysfunction and glomerulosclerosis than intact, ie, estrogen sufficient agematched female mice. Ovariectomized ROP Os/؉ exhibited increased accumulation of extracellular matrix, predominantly of laminin, and a marked distortion of the glomerular architecture. We found an increase in macrophage infiltration in the mesangium of ovariectomized ROP Os/؉. Estrogen deficiency decreased glomerular estrogen receptor expression in ROP Os/؉ mice, which we had previously found to be low in the parental ROP strain. Thus, although physiological estrogen levels in young ROP Os/؉ mice could not prevent the development of glomerulosclerosis, estrogen deficiency accelerated the progression of glomerular scarring in this mouse strain. This suggests that estrogen replacement will slow but not prevent the progression of glomerulosclerosis. It underscores the importance of the genetic composition of individuals that determines the susceptibility to diseases as well as the response to treatment. Estrogen deficiency may contribute to the development and progression of glomerulosclerosis in postmenopausal women. This is suggested by data from the United States Renal Data System, which show that the female to male ratio of patients with end-stage renal disease because of diabetes increases sharply in the postmenopausal age groups, especially of those from ethnic minorities. 1 The United States Renal Data System data as well as additional genetic and epidemiological studies also suggest that genetic factors play an important role in the susceptibility to develop glomerulosclerosis and the progression to end-stage renal disease. 2,3 The responsiveness to estrogens, which is primarily determined by the level of estrogen receptor (ER) expression, 4 could be controlled by genetic traits related to those that determine the susceptibility to glomerular scarring. We have previously shown that the renal glomerulus is a direct target tissue for estrogens. 5,6 Human and mouse mesangial cells, which play a central role in the pathogenesis of glomerulosclerosis, express both ER subtypes ␣ and ␤. 5 We reported that these ERs were transcriptionally active and that estrogens positively regulated ER expression in mesangial cells. 5 We also found that estrogens provided protection from glomerulosclerosis by regulating genes involved in extracellular matrix (ECM) turnover in a manner leading to the prevention of ECM accumulation in the mesangium. 5,6 Estrogen treatment increased the expression and activity of matrix metalloproteinase (MMP)-9 in mesangial cells isolated from glomeruloscler...

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“…Indeed, basal arterial blood pressure increases more in ERβ −/− mice during aging than in age‐matched control mice 49. In addition, the pharmacological activation of ERβ leads to blood pressure lowering in spontaneously hypertensive rats with reduced myocardial hypertrophy 50.…”

Section: Discussionmentioning

confidence: 99%

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

Guivarch

Buscato

Guihot

et al. 2018

JAHA

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BackgroundAlthough 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 ResultsUsing 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.ConclusionsAltogether, 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.

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Abnormal Vascular Function and Hypertension in Mice Deficient in Estrogen Receptor β

Cited by 453 publications

References 25 publications

Aromatase-Deficient (ArKO) Mice Have Reduced Blood Pressure and Baroreflex Sensitivity

Aromatase-Deficient (ArKO) Mice Have Reduced Blood Pressure and Baroreflex Sensitivity

Estrogen Deficiency Accelerates Progression of Glomerulosclerosis in Susceptible Mice

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

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