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Research Resource: Rapid Recruitment of Temporally Distinct Vascular Gene Sets by Estrogen

Molecular Cardiology Research Institute (K.K.S., I.Z.J., L.I., A.D., M.A., B.N., M.E.M.), Tufts Medical Center, Boston, Massachusetts 02111; Department of Biology (U.H.), Program in Bioinformatics, Boston University, Boston, Massachusetts 02215; and Instituto di Ricovero e Cura a Carattere Scientifico (G.R.), San Raffaele Pisana, 00163 Rome, Italy

Address all correspondence and requests for reprints to: Michael E. Mendelsohn, M.D., Tufts Medical Center, 800 Washington Street, Box 080, Boston, Massachusetts 02111. E-mail: mmendelsohn{at}tuftsnemc.org.

ABSTRACT

Cardiovascular disease is the leading cause of mortality for both men and women in developed countries. The sex steroid hormone estrogen is required for normal vascular physiology. Estrogen functions by binding to intracellular estrogen receptors (ER), ER and ERβ, ligand-activated transcription factors that are expressed in both vascular endothelial and smooth muscle cells. We recently demonstrated that long-term (8 d) estrogen treatment in vivo in mice recruits distinct vascular gene sets mediated by ER and ERβ and that the promoters from these gene sets are enriched for binding sites of specific transcription factors, leading to the hypothesis that estrogen initiates a cascade of early transcriptional events that modulate gene expression in the vasculature. Here we test this hypothesis using gene expression profiling to examine initial transcriptional events (2–8 h) mediated by estrogen in blood vessels. Our data reveal that 1) estrogen regulates temporally distinct cascades of vascular gene expression, 2) initially, estrogen-mediated vascular gene repression predominates, 3) the earliest estrogen-recruited gene program is enriched in vascular transcription factors that can interact with binding sites present in estrogen-regulated vascular genes recruited subsequently, and 4) estrogen-regulated genes recruited next have specific functions, including lipid metabolism and cellular growth and proliferation that are potentially important for estrogen’s known vascular functions. In summary, estrogen directly and rapidly recruits specific transcriptional factors that then propagate distinct cascades of gene expression. These data define the temporal recruitment of specific vascular genes by estrogen and enable further analysis of the mechanisms by which estrogen directly regulates vascular function.

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Ligands:   17β-Estradiol