title: Rapid estrogen receptor signaling is essential for the protective effects of estrogen against vascular injury.
abstract: BACKGROUND
  Clinical trial and epidemiological data support that the cardiovascular effects of estrogen are complex, including a mixture of both potentially beneficial and harmful effects. In animal models, estrogen protects females from vascular injury and inhibits atherosclerosis. These effects are mediated by estrogen receptors (ERs), which, when bound to estrogen, can bind to DNA to directly regulate transcription. ERs can also activate several cellular kinases by inducing a rapid nonnuclear signaling cascade. However, the biological significance of this rapid signaling pathway has been unclear.
  
  
  RESULTS
  In the present study, we develop a novel transgenic mouse in which rapid signaling is blocked by overexpression of a peptide that prevents ERs from interacting with the scaffold protein striatin (the disrupting peptide mouse). Microarray analysis of ex vivo treated mouse aortas demonstrates that rapid ER signaling plays an important role in estrogen-mediated gene regulatory responses. Disruption of ER-striatin interactions also eliminates the ability of estrogen to stimulate cultured endothelial cell migration and to inhibit cultured vascular smooth muscle cell growth. The importance of these findings is underscored by in vivo experiments demonstrating loss of estrogen-mediated protection against vascular injury in the disrupting peptide mouse after carotid artery wire injury.
  
  
  CONCLUSIONS
  Taken together, these results support the concept that rapid, nonnuclear ER signaling contributes to the transcriptional regulatory functions of ER and is essential for many of the vasoprotective effects of estrogen. These findings also identify the rapid ER signaling pathway as a potential target for the development of novel therapeutic agents.
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Bernelot Moens
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Schnitzler
authors.forename: Moriah
authors.initials: M
authors.lastname: Nickerson
authors.forename: Huiming
authors.initials: H
authors.lastname: Guo
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ueda
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Aronovitz
authors.forename: Heather
authors.initials: H
authors.lastname: Nickerson
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Baur
authors.forename: Ulla
authors.initials: U
authors.lastname: Hansen
authors.forename: Lakshmanan K
authors.initials: LK
authors.lastname: Iyer
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D019556:COS Cells; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D010052:Ovariectomy; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology*; D059467:Transcriptome
chemical_list: D047628:Estrogen Receptor alpha; D004958:Estradiol