title: Enhanced age-dependent cerebrovascular dysfunction is mediated by adaptor protein p66Shc.
abstract: BACKGROUND
  Aging is an independent risk factor for cardiovascular and cerebrovascular disease. To date, little is known about the mechanisms of aging of cerebral arteries and whether the aging gene p66(Shc) is implicated in it. The present study was designed to assess age-induced vascular dysfunction in cerebral and systemic arteries of wild type (wt) and p66(Shc-/-) mice.
  
  
  METHODS
  Basilar arteries and size matched second order femoral arteries of 3-month (3M), 6-month (6M) and 2-year old (2Y) mice were studied in wt and p66(Shc-/-) mice. To assess vascular function, arterial rings mounted in a myograph for isometric tension recordings were exposed to increasing concentrations of acetylcholine and sodium nitroprusside. Reactive oxygen species (ROS) generation was assessed in femoral and basilar arteries using the spin trap 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine.
  
  
  RESULTS
  In wt mice, endothelial function of the femoral artery was not affected by age unlike in the basilar artery where an age-dependent dysfunction was observed. In p66(Shc-/-) a similar response was observed in the femoral artery; however, age-dependent endothelial dysfunction of the basilar artery was blunted as compared to wt. Levels of ROS were comparable in the femoral arteries of 3M and 2Y of wt and p66(Shc-/-) mice. Differently, ROS levels in the basilar artery of wt mice were strongly increased by age unlike in p66(Shc-/-) mice where they remained comparable irrespective of age.
  
  
  CONCLUSIONS
  Endothelial function in cerebral arteries, but not in size-matched systemic ones, is heavily impaired by aging. This process is paralleled by an increased ROS production and is mediated by the p66(Shc) gene.
authors.affiliation: Center of Molecular Cardiology, University of Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZHIP), University of Zurich, Zurich, Switzerland; Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Center of Molecular Cardiology, University of Zurich, Zurich, Switzerland; Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Savarese
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Perrone-Filardi
authors.affiliation: Center of Molecular Cardiology, University of Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZHIP), University of Zurich, Zurich, Switzerland.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.affiliation: Center of Molecular Cardiology, University of Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZHIP), University of Zurich, Zurich, Switzerland.
authors.forename: Giovanni G
authors.initials: GG
authors.lastname: Camici
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001488:Basilar Artery / Q000378:metabolism / Q000473:pathology; D002561:Cerebrovascular Disorders / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005263:Femoral Artery / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D055765:Shc Signaling Adaptor Proteins / Q000096:biosynthesis / Q000502:physiology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
keywords: Aging; Endothelial dysfunction; ROS; p66(Shc)