title: Endothelial TRPV4 channels mediate dilation of cerebral arteries: impairment and recovery in cerebrovascular pathologies related to Alzheimer's disease.
abstract: OBJECTIVE
  Transient receptor potential vanilloid type 4 (TRPV4) channels are expressed in brain endothelial cells, but their role in regulating cerebrovascular tone under physiological and pathological conditions is still largely unknown.
  
  
  METHODS
  Wild-type (WT) mice and mice that overexpress a mutated form of the human amyloid precursor protein (APP mice, model of increased amyloid β), a constitutively active form of TGF-β1 (TGF mice, model of cerebrovascular fibrosis) or both (APP/TGF mice) were used. Dilations to the selective TRPV4 channel opener GSK1016790A (GSK) or to ACh were measured in posterior cerebral artery segments.
  
  
  RESULTS
  Both GSK- and ACh-induced dilations virtually disappeared following endothelium denudation in WT mice. These responses were impaired in vessels from APP, TGF and APP/TGF mice compared with WT. Pre-incubation of WT vessels with the selective TRPV4 channel blocker HC-067047, or with small-conductance (SK channel, apamin) and/or intermediate-conductance (IK channel, charybdotoxin, ChTx) Ca(2+) -sensitive K(+) channel blocker abolished GSK-induced dilations and massively decreased those induced by ACh. These treatments had no or limited effects on ACh-induced dilation in vessels from APP, TGF or APP/TGF mice, and IK and SK channel function was preserved in transgenic mice. Antioxidant superoxide dismutase or catalase normalized GSK- and ACh-mediated dilations only in APP brain arteries.
  
  
  CONCLUSIONS
  We conclude that endothelial TRPV4 channels mediate ACh-induced dilation in cerebral arteries, that they are impaired in models of cerebrovascular pathology and that they are sensitive, albeit in the reversible manner, to amyloid β-induced oxidative stress.
authors.affiliation: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
authors.forename: Luqing
authors.initials: L
authors.lastname: Zhang
authors.forename: Panayiota
authors.initials: P
authors.lastname: Papadopoulos
authors.forename: Edith
authors.initials: E
authors.lastname: Hamel
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002561:Cerebrovascular Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D018384:Oxidative Stress; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D050916:TRPV Cation Channels; D053773:Transforming Growth Factor beta1; C486576:Trpv4 protein, mouse; D014665:Vasodilator Agents
keywords: TGF-β1; amyloid β peptide; cerebral artery; endothelium; oxidative stress; vasodilation
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