title: Rapid recruitment of temporally distinct vascular gene sets by estrogen.
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), ERalpha and ERbeta, 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 ERalpha and ERbeta 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.
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, 800 Washington Street, Box 080, Boston, Massachusetts 02111, USA.
authors.forename: Katrin K
authors.initials: KK
authors.lastname: Schnoes
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Jaffe
authors.forename: Lakshmanan
authors.initials: L
authors.lastname: Iyer
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dabreo
authors.forename: Mark
authors.initials: M
authors.lastname: Aronovitz
authors.forename: Brenna
authors.initials: B
authors.lastname: Newfell
authors.forename: Ulla
authors.initials: U
authors.lastname: Hansen
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rosano
authors.forename: Michael E
authors.initials: ME
authors.lastname: Mendelsohn
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000209:etiology / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000172:deficiency / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D005810:Multigene Family / Q000187:drug effects; D012727:Sex Characteristics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D014157:Transcription Factors; D004958:Estradiol
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