TY - JOUR TI - Neuroprotective effects of TRPA1 channels in the cerebral endothelium following ischemic stroke AU - Pires, Paulo Wagner AU - Earley, Scott A2 - Kleinfeld, David A2 - Aldrich, Richard VL - 7 PY - 2018 DA - 2018/09/21 SP - e35316 C1 - eLife 2018;7:e35316 DO - 10.7554/eLife.35316 UR - https://doi.org/10.7554/eLife.35316 AB - 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. KW - TRPA1 KW - endothelium-dependent dilation KW - hypoxia KW - Ca2+ influx KW - ischemic strokes KW - middle cerebral artery occlusion JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -