Neuroprotective effects of TRPA1 channels in the cerebral endothelium following ischemic stroke.

Paulo Wagner Pires,Scott Earley

doi:10.7554/elife.35316

Abstract

Hypoxia and ischemia are linked to oxidative stress, which can activate the oxidant-sensitive transient receptor potential ankyrin 1 (TRPA1) channel in cerebral artery endothelial cells, leading to vasodilation. We hypothesized that TRPA1 channels in endothelial cells are activated by hypoxia-derived reactive oxygen species, leading to cerebral artery dilation and reduced ischemic damage. Using isolated cerebral arteries expressing a Ca2+ biosensor in endothelial cells, we show that 4-hydroxynonenal and hypoxia increased TRPA1 activity, detected as TRPA1 sparklets. TRPA1 activity during hypoxia was blocked by antioxidants and by TRPA1 antagonism. Hypoxia caused dilation of cerebral arteries, which was disrupted by antioxidants, TRPA1 blockade and by endothelial cell-specific Trpa1 deletion (Trpa1 ecKO mice). Loss of TRPA1 channels in endothelial cells increased cerebral infarcts, whereas TRPA1 activation with cinnamaldehyde reduced infarct in wildtype, but not Trpa1 ecKO, mice. These data suggest that endothelial TRPA1 channels are sensors of hypoxia leading to vasodilation, thereby reducing ischemic damage.

Highlights

Interruption of regional blood flow within the brain can rapidly cause irreparable neuronal damage
We investigated the functional importance of transient receptor potential ankyrin 1 (TRPA1) channels in the cerebral endothelium under pathophysiological conditions
We found that acute hypoxic exposure induced an increase in TRPA1 sparklet frequency in the endothelium of intact cerebral pial arteries and penetrating arterioles that caused dilation

Summary

Introduction

Interruption of regional blood flow within the brain can rapidly cause irreparable neuronal damage. G-protein-coupled receptors and ion channels present on the endothelial cells and vascular smooth muscle cells (SMCs) that form the walls of cerebral blood vessels initiate many of the signaling cascades that enable these intrinsic adaptive processes. The specific cellular pathways responsible for cerebrovascular homeostasis are of considerable interest as potential therapeutic targets for diseases associated with impaired blood flow regulation within the brain, such as stroke and vascular cognitive impairment; these pathways remain incompletely understood. We recently reported that transient receptor potential ankyrin 1 (TRPA1) cation channels are present in the endothelium of arteries within the brain, but not in other arterial beds (Sullivan et al, 2015), suggesting a specialized role for these channels in cerebral blood flow regulation. We investigated the endogenous adaptive and protective functions of TRPA1 channels within the cerebral vasculature

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