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

Department of Biology (R.O., U.H.), Program in Bioinformatics (M.E.S., U.H.), and Department of Biomedical Engineering (J.B.), Boston University, Boston, Massachusetts 02215; Molecular Cardiology Research Institute (K.K., I.Z.J., R.H.K., M.E.M.), Tufts-New England Medical Center, Boston, Massachusetts 02111; CSAIL (J.B.), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; and Institute of Endocrinology (P.G.V.M.), University of Milan, 20133 Milan, Italy

Address all correspondence and requests for reprints to: Dr. Ulla Hansen, 5 Cummington Street, Boston Massachusetts 02215. 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 (ER) and ß (ERß), 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 the expression of which is regulated by long-term (1 wk) estrogen treatment. The ER subtype dependence of the alterations in gene expression was characterized by parallel gene expression profiling experiments in ER-deficient [ER knockout (ERKO)] and ERß-deficient (ERßKO) mice. Importantly, these data revealed that ER- and ERß-dependent pathways regulate distinct and largely nonoverlapping sets of genes. Whereas ER is essential for most of the estrogen-mediated increase in gene expression in wild-type aortas, ERß mediates the large majority (nearly 90%) of estrogen-mediated decreases in gene expression. Biological functions of the estrogen-regulated genes include extracellular matrix synthesis, in addition to electron transport in the mitochondrion and reactive oxygen species pathways. Of note, the estrogen/ERß pathway mediates down-regulation 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 coexpressed 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol

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