Endogenously‐generated lipid peroxidation products dilate rat cerebral arteries by activating TRPA1 channels in the endothelium

Abstract

The Ca2+‐permeable ankyrin (A) transient receptor potential (TRP) channel TRPA1 is activated by a variety of pungent and irritating electrophilic substances. TRPA1 channels are present in the cerebral artery endothelium, but physiological activators of the channel in this tissue are not known. We tested the hypothesis that lipid peroxidation products (LPP) generated by reactive oxygen species (ROS) are endogenous activators of TRPA1 in the cerebral endothelium. We found that NADPH, a substrate of the ROS‐producing enzyme NADPH oxidase (NOX), increased TRPA1 Ca2+sparklet frequency in primary cerebral artery endothelial cells (0.04 ± 0.02 Hz before vs. 0.28 ± 0.08 Hz after, n = 20–30). NADPH also dilated pressurized (80 mmHg) rat cerebral arteries in a concentration‐dependent manner (EC50 = 1.2 μM). This response was diminished by the selective TRPA1 antagonist HC‐030031 (HC) (61.3 ± 21.6% dilation (NADPH) vs. 8.7 ± 16.2% dilation (HC + NADPH), n = 3). The LPP 4‐hydroxy‐nonenal (4‐HNE) also caused cerebral artery dilation (EC50 = 8.4 μM) that was abolished by HC (51.4 ± 7.8% dilation (4‐HNE) vs. 0.0 ± 11.6 % (HC + 4‐HNE), n = 5). Immunolabeling of rat cerebral arteries demonstrates co‐localization of TRPA1, NOX2, and 4‐HNE in myoendothelial junction (MEJ) sites. Together, our findings suggest that NOX‐derived LPP dilate cerebral arteries by activating TRPA1 in MEJs. HL091905.