Endothelial TRPV4 channels mediate dilation of cerebral arteries: impairment and recovery in cerebrovascular pathologies related to Alzheimer's disease

Br J Pharmacol. 2013 Oct;170(3):661-70. doi: 10.1111/bph.12315.


Background and purpose: 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.

Experimental approach: 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.

Key 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.

Conclusion and implications: 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.

Keywords: TGF-β1; amyloid β peptide; cerebral artery; endothelium; oxidative stress; vasodilation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / physiopathology
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Antioxidants / pharmacology
  • Cerebral Arteries / drug effects
  • Cerebral Arteries / metabolism*
  • Cerebral Arteries / physiopathology
  • Cerebrovascular Disorders / genetics
  • Cerebrovascular Disorders / metabolism*
  • Cerebrovascular Disorders / physiopathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / physiopathology
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Oxidative Stress
  • Signal Transduction
  • TRPV Cation Channels / metabolism*
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism
  • Vasodilation* / drug effects
  • Vasodilator Agents / pharmacology


  • APP protein, human
  • Amyloid beta-Protein Precursor
  • Antioxidants
  • TRPV Cation Channels
  • Transforming Growth Factor beta1
  • Trpv4 protein, mouse
  • Vasodilator Agents