Localized TRPA1 channel Ca2+ signals stimulated by reactive oxygen species promote cerebral artery dilation

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Science Signaling  06 Jan 2015:
Vol. 8, Issue 358, pp. ra2
DOI: 10.1126/scisignal.2005659

Blood Vessel Dilation with Peroxidized Lipids

Cerebral arteries must maintain constant blood flow to the brain even though blood pressure fluctuates constantly. Sullivan et al. characterized a signaling pathway that is specific to the endothelial cells that line cerebral arteries. Reactive oxygen species (ROS) cause lipid peroxidation. In endothelial cells in cerebral arteries, locally produced ROS oxidized lipids, which triggered calcium influx through the ion channel TRPA1. In turn, this calcium influx activated a potassium-permeable channel, resulting in dilation of cerebral arteries.


Reactive oxygen species (ROS) can have divergent effects in cerebral and peripheral circulations. We found that Ca2+-permeable transient receptor potential ankyrin 1 (TRPA1) channels were present and colocalized with NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase 2 (NOX2), a major source of ROS, in the endothelium of cerebral arteries but not in other vascular beds. We recorded and characterized ROS-triggered Ca2+ signals representing Ca2+ influx through single TRPA1 channels, which we called “TRPA1 sparklets.” TRPA1 sparklet activity was low under basal conditions but was stimulated by NOX-generated ROS. Ca2+ entry during a single TRPA1 sparklet was twice that of a TRPV4 sparklet and ~200 times that of an L-type Ca2+ channel sparklet. TRPA1 sparklets representing the simultaneous opening of two TRPA1 channels were more common in endothelial cells than in human embryonic kidney (HEK) 293 cells expressing TRPA1. The NOX-induced TRPA1 sparklets activated intermediate-conductance, Ca2+-sensitive K+ channels, resulting in smooth muscle hyperpolarization and vasodilation. NOX-induced activation of TRPA1 sparklets and vasodilation required generation of hydrogen peroxide and lipid-peroxidizing hydroxyl radicals as intermediates. 4-Hydroxy-nonenal, a metabolite of lipid peroxidation, also increased TRPA1 sparklet frequency and dilated cerebral arteries. These data suggest that in the cerebral circulation, lipid peroxidation metabolites generated by ROS activate Ca2+ influx through TRPA1 channels in the endothelium of cerebral arteries to cause dilation.

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