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This version published online on March 20, 2007
Molecular Endocrinology, doi:10.1210/me.2006-0497
Molecular Endocrinology Vol. 0, No. 2007 200604971-
doi:10.1210/me.2006-0497
Copyright © 2007 by the Endocrine Society.
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Submitted on November 27, 2006
Accepted on March 12, 2007

Estrogen Receptors {alpha} and {beta} Mediate Distinct Pathways of Vascular Gene Expression, Including Genes Involved in Mitochondrial Electron Transport and Generation of Reactive Oxygen Species

Raegan O'Lone, Katrin Knorr, Iris Z. Jaffe, Michael E. Schaffer, Paolo G.V. Martini, Richard H. Karas, Jadwiga Bienkowska, Michael E. Mendelsohn, and Ulla Hansen*

Department of Biology, Boston University, Boston, MA; Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, MA; Bioinformatics Program, Boston University, Boston, MA; Department of Biomedical Engineering, Boston, University, Boston, MA and CSAIL, Massachusetts Institute of Technology, Cambridge MA; Institute of Endocrinology, University of Milano, Italy

* To whom correspondence should be addressed. E-mail: uhansen{at}bu.edu.

Estrogen plays an important role in the regulation of vascular tone and in the pathophysiology of cardiovascular disease. Physiological effects of estrogen are mediated through estrogen receptors {alpha} (ER{alpha}) and {beta} (ER{beta}), which are both expressed in vascular smooth muscle and endothelial cells. However, the molecular pathways mediating estrogen effects in blood vessels are not well defined. We have performed gene expression profiling in the mouse aorta to identify comprehensive gene sets whose expression is regulated by long-term (one week) estrogen treatment. The ER subtype-dependence of the alterations in gene expression was characterized by parallel gene expression profiling experiments in ER{alpha}-deficient (ER{alpha}KO) and ER{beta}-deficient (ER{beta}KO) mice. Importantly, these data revealed that ER{alpha}- and ER{beta}-dependent pathways regulate distinct and largely non-overlapping sets of genes. Whereas ER{alpha} is essential for most of the estrogen-mediated increase in gene expression in wild type aortas, ER{beta} mediates the large majority (nearly 90%) of estrogen-mediated decreases in gene expression. Biological functions of the estrogen-regulated genes include extracellular matrix synthesis, as well as electron transport in the mitochondrion and reactive oxygen species pathways. Of note, the estrogen/ER{beta} pathway mediates downregulation of mRNAs for nuclear-encoded subunits in each of the major complexes of the mitochondrial respiratory chain. Several estrogen-regulated genes also encode transcription factors. Computational analysis of promoters from co-expressed genes revealed overrepresentation of binding sites for such factors, lending support for an estrogen regulatory transcriptional network in the vasculature. Overall, these findings provide a foundation for understanding the molecular basis for estrogen effects on vasculature gene expression.
Key words: Estrogen receptor • gene expression profiling • vasculature • mouse • transcription factors • regulatory network • mitochondrial respiratory chain • reactive oxygen species

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ
Ligands:   17β-Estradiol



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