Abstract 141: Endothelial TRPA1 Channel is Protective Against Ischemia and Hemorrhagic Strokes in Mice

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The transient receptor potential ankyrin 1 (TRPA1) cation channel is more selective for Ca2+ versus Na+ ions (∼8:1). We showed that TRPA1 is located in the endothelium of cerebral arteries (eTRPA1) and that reactive oxygen species (ROS)-induced channel activity generates localized Ca2+ signals (TRPA1 sparklets) that initiate endothelium-dependent hyperpolarization and vasorelaxation. Cerebrovascular disease is associated with increased ROS generation and oxidative stress. Thus, we hypothesized that eTRPA1 activity is protective against stroke. Tissue-specific deletion of eTRPA1 in mice was achieved using the Cre-recombinase (Tie2 promoter) / loxP system. Ischemic strokes were induced by permanent middle cerebral artery occlusion (pMCAO). Neurological function after pMCAO was assessed by a modified neurological severity scale, ranging from 0 to 4 (0: normal behavior; 1: failure to extend contralateral paw; 2: circling; 3: rolling to one side; 4: stupor). Deletion of eTRPA1 increased post-stroke (24 hours) neurological damage in eTRPA1-/- versus WT mice, as shown by a higher severity score (2.6±0.4 vs 3.8±0.2, p<0.05), and larger infarct size (%hemisphere infarcted: 45±7 vs 62±4%, p0.05, N=8), eTRPA1-/- mice were significantly more susceptible to hemorrhagic strokes compared to WT. Kaplan-Meyer survival plots showed a higher survival rate for WT vs eTRPA1-/- at day 10 (61 vs 54%), day 15 (44 vs 21%) and day 20 (22 vs 8%) (p<0.05, N=25). All of the eTRPA1-/- mice suffered hemorrhagic strokes by day 22, whereas some of the WT mice survived until day 52. Further, eTRPA1-/- mice showed a higher number of hemorrhagic lesions in the cerebral cortex when compared to WT (12±4 vs 23±4 lesions per animal, p<0.05, N=25 mice per group). These data suggest that eTRPA1 protects against major cerebrovascular accidents and may be considered as a therapeutic target for reducing cerebral infarct after ischemia and as a preventive agent against hemorrhagic strokes.

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