title: Rapid estrogen receptor signaling mediates estrogen-induced inhibition of vascular smooth muscle cell proliferation.
abstract: OBJECTIVE
  The proliferation of vascular smooth muscle cells (VSMCs) plays a crucial role in vascular diseases, such as atherosclerosis and restenosis, after percutaneous coronary intervention. Many studies have shown that estrogen inhibits VSMC proliferation in response to vascular injury in the mouse carotid injury model. However, the mechanisms that mediate these effects remain unclear. Here, we investigated the mechanisms by which estrogen inhibits VSMC proliferation.
  
  
  RESULTS
  We established a novel transgenic mouse line, referred to as the disrupting peptide mice, in which rapid estrogen receptor (ER)-mediated signaling is abolished by overexpression of a peptide that prevents the ER from forming a signaling complex necessary for rapid signaling. Carotid artery VSMCs from disrupting peptide mice or littermate wild-type female mice were obtained by the explant method. In VSMCs derived from wild-type mice, estrogen significantly inhibited VSMC proliferation. Phosphorylation levels of Akt and extracellular regulated kinase induced by platelet derived growth factor were significantly inhibited by estrogen pretreatment. Estrogen enhanced complex formation between ERα and protein phosphatase 2A (PP2), and enhanced PP2A activity. The blockade of PP2A activity abolished the estrogen-induced antiproliferative effect on VSMCs. In contrast, none of these effects of estrogen observed in the wild-type VSMCs were observed in VSMCs derived from disrupting peptide mice. These results support that rapid, non-nuclear ER signaling is required for estrogen-induced inhibition of VSMC proliferation, and further that PP2A activation by estrogen mediates estrogen-induced antiproliferative effects.
  
  
  CONCLUSIONS
  These findings support that PP2A activation via rapid, non-nuclear ER signaling may be a novel target for therapeutic approaches to inhibit VSMC proliferation, which plays a central role in atherosclerosis and restenosis.
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ueda
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.forename: Wendy
authors.initials: W
authors.lastname: Baur
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Aronovitz
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D000071636:Protein Phosphatase 2C; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D002148:Calmodulin-Binding Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C491924:Strn protein, mouse; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
keywords: cardiovascular diseases; hormones; molecular biology; signal transduction