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Science 295 (5554): 505-508

Copyright © 2002 by the American Association for the Advancement of Science

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

Yan Zhu,1 Zhao Bian,23 Ping Lu,1 Richard H. Karas,1 Lin Bao,1 Daniel Cox,1 Jeffrey Hodgin,4 Philip W. Shaul,5 Peter Thorén,3 Oliver Smithies,4 Jan-Åke Gustafsson,2 Michael E. Mendelsohn1*

Blood vessels express estrogen receptors, but their role in cardiovascular physiology is not well understood. We show that vascular smooth muscle cells and blood vessels from estrogen receptor beta  (ERbeta )-deficient mice exhibit multiple functional abnormalities. In wild-type mouse blood vessels, estrogen attenuates vasoconstriction by an ERbeta -mediated increase in inducible nitric oxide synthase expression. In contrast, estrogen augments vasoconstriction in blood vessels from ERbeta -deficient mice. Vascular smooth muscle cells isolated from ERbeta -deficient mice show multiple abnormalities of ion channel function. Furthermore, ERbeta -deficient mice develop sustained systolic and diastolic hypertension as they age. These data support an essential role for ERbeta in the regulation of vascular function and blood pressure.

1 Molecular Cardiology Research Institute, New England Medical Center and Department of Medicine, Tufts University School of Medicine, Boston, MA 02111, USA.
2 Department of Medical Nutrition and Center for Biotechnology, Novum, Huddinge University Hospital, 141 86 Huddinge, Sweden.
3 Department of Physiology and Pharmacology, 171 77, Karolinska Institute, Stockholm, Sweden.
4 Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA.
5 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
*   To whom correspondence should be addressed. E-mail: mmendelsohn{at}

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Circ. Res. 93, 1142-1145
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Impaired Acetylcholine-Induced Release of Nitric Oxide in the Aorta of Male Aromatase-Knockout Mice: Regulation of Nitric Oxide Production by Endogenous Sex Hormones in Males.
M. Kimura, K. Sudhir, M. Jones, E. Simpson, A.-M. Jefferis, and J. P.F. Chin-Dusting (2003)
Circ. Res. 93, 1267-1271
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Regulation of nitric oxide-dependent vasodilation in coronary arteries of estrogen receptor-{alpha}-deficient mice.
J. M. Muller-Delp, D. B. Lubahn, K. E. Nichol, B. J. Philips, E. M. Price, E. M. Curran, and M. H. Laughlin (2003)
Am J Physiol Heart Circ Physiol 285, H2150-H2157
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Improvement of Endothelial Dysfunction by Selective Estrogen Receptor-{alpha} Stimulation in Ovariectomized SHR.
J. Widder, T. Pelzer, C. von Poser-Klein, K. Hu, V. Jazbutyte, K.-H. Fritzemeier, C. Hegele-Hartung, L. Neyses, and J. Bauersachs (2003)
Hypertension 42, 991-996
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Attenuated Responses to Angiotensin II in Follitropin Receptor Knockout Mice, a Model of Menopause-Associated Hypertension.
D. Javeshghani, R. M. Touyz, M. R. Sairam, A. Virdis, M. F. Neves, and E. L. Schiffrin (2003)
Hypertension 42, 761-767
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Specific Contribution of Estrogen Receptors on Mitogen-Activated Protein Kinase Pathways and Vascular Cell Activation.
P. Geraldes, M. G. Sirois, and J.-F. Tanguay (2003)
Circ. Res. 93, 399-405
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Diabetes Undermines Estrogen Control of Inducible Nitric Oxide Synthase Function in Rat Aortic Smooth Muscle Cells Through Overexpression of Estrogen Receptor-{beta}.
A. Maggi, A. Cignarella, A. Brusadelli, C. Bolego, C. Pinna, and L. Puglisi (2003)
Circulation 108, 211-217
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Cardiovascular Risk Factors and Urinary Albumin: Vive la Petite Difference.
E. Ritz (2003)
J. Am. Soc. Nephrol. 14, 1415-1416
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Peroxisome Proliferator-Activated Receptor-{gamma} Coactivator-1 Gene Locus: Associations with Hypertension in Middle-Aged Men.
H. Oberkofler, B. Holzl, H. Esterbauer, M. Xie, B. Iglseder, F. Krempler, B. Paulweber, and W. Patsch (2003)
Hypertension 41, 368-372
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Proximal Events in Signaling by Plasma Membrane Estrogen Receptors.
M. Razandi, A. Pedram, S. T. Park, and E. R. Levin (2003)
J. Biol. Chem. 278, 2701-2712
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Nonnuclear Actions of Estrogen.
K. J. Ho and J. K. Liao (2002)
Arterioscler Thromb Vasc Biol 22, 1952-1961
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Nonlinear partial differential equations and applications: Involvement of estrogen receptor {beta} in terminal differentiation of mammary gland epithelium.
C. Forster, S. Makela, A. Warri, S. Kietz, D. Becker, K. Hultenby, M. Warner, and J.-A. Gustafsson (2002)
PNAS 99, 15578-15583
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The Atheroprotective Effect of Dietary Soy Isoflavones in Apolipoprotein E-/- Mice Requires the Presence of Estrogen Receptor-{alpha}.
M. R. Adams, D. L. Golden, T. C. Register, M. S. Anthony, J. B. Hodgin, N. Maeda, and J.K. Williams (2002)
Arterioscler Thromb Vasc Biol 22, 1859-1864
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Clues to understanding the role of estrogen receptors in mediating cardiovascular protection.
X.-J. Du (2002)
Cardiovasc Res 56, 4-7
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Expression of estrogen receptor subtypes and neuronal nitric oxide synthase in neutrophils from women and men: Regulation by estrogen.
L. Molero, M. Garcia-Duran, J. Diaz-Recasens, L. Rico, S. Casado, and A. Lopez-Farre (2002)
Cardiovasc Res 56, 43-51
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Estrogen increases iNOS expression in the ovine coronary artery.
J. L. Mershon, R. S. Baker, and K. E. Clark (2002)
Am J Physiol Heart Circ Physiol 283, H1169-H1180
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Steroid Receptor Coactivator-3 Is Required for Inhibition of Neointima Formation by Estrogen.
Y. Yuan, L. Liao, D. A. Tulis, and J. Xu (2002)
Circulation 105, 2653-2659
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Role for Estrogen Receptors in Hypertension.
Journal Watch Cardiology 2002, 6
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