Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-Activated K+ channels.
Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-Activated K+ channels.
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DOI：
10.1161/circresaha.108.189530
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发表时间：
2009-04-24
影响因子：
20.1
通讯作者：
Crnich R
中科院分区：
文献类型：
--
作者：
Earley S;Gonzales AL;Crnich R
尽管内皮细胞内[Ca~(2+)]的变化调节内皮依赖的血管扩张途径已被证实，但这些细胞内负责Ca~(2+)内流的离子通道的分子特性尚不清楚。Ankyrin(A)瞬时受体潜力(Trp)亚家族的唯一成员TRPA1是一种钙离子渗透性非选择性阳离子通道，由亲电化合物激活，如丙烯连素(催泪气体)、大蒜素(大蒜)和异硫氰酸烯丙酯(AITC)(芥子油)。目前的研究验证了一种假说，即通过TRPA1的钙离子内流导致内皮依赖性血管扩张。在分离的加压脑动脉上检测TRPA1活性对血管张力的影响。AITC可诱导肌源性张力的加压血管的浓度依赖性扩张，并伴随着细胞内[Ca~(2+)]的相应降低。当动脉腔内存在TRPA1通道阻滞剂HC-030031时，血管内皮细胞破裂和TRPA1通道阻滞剂HC-030031可减弱血管紧张素转换酶抑制剂诱导的血管扩张。TRPA1通道存在于天然内皮细胞中，定位于血管平滑肌细胞近端的内皮细胞膜突起。AITC诱导的扩张对一氧化氮合酶或环氧合酶抑制不敏感，但可被小电导和中等电导的钙激活K+通道阻断剂阿帕明和TRAM34阻断。内向整流性K+(KIR)通道的阻断剂BaCl2也能抑制AITC诱导的血管扩张。AITC诱导的平滑肌细胞超极化可被阿帕明和TRAM34阻断。我们认为，通过内皮细胞内皮细胞激活的K+通道和KIR通道，通过内皮细胞内流的TRPA1通道引起的脑血管扩张作用。
Although it is well established that changes in endothelial intracellular [Ca2+] regulate endothelium-dependent vasodilatory pathways, the molecular identities of the ion channels responsible for Ca2+ influx in these cells are not clearly defined. The sole member of the ankyrin (A) transient receptor potential (TRP) subfamily, TRPA1, is a Ca2+-permeable non-selective cation channel activated by electrophilic compounds such as acrolien (tear gas), allicin (garlic) and allyl isothiocyanate (AITC) (mustard oil). The current study examines the hypothesis that Ca2+ influx via TRPA1 causes endothelium-dependent vasodilation. The effects of TRPA1 activity on vascular tone were examined using isolated, pressurized cerebral arteries. AITC induced concentration-dependent dilation of pressurized vessels with myogenic tone that was accompanied by a corresponding decrease in smooth muscle intracellular [Ca2+]. AITC-induced dilation was attenuated by disruption of the endothelium and when the TRPA1 channel blocker HC-030031 was present in the arterial lumen. TRPA1 channels were found to be present in native endothelial cells, localized to endothelial cell membrane projections proximal to vascular smooth muscle cells. AITC-induced dilation was insensitive to nitric oxide synthase or cyclooxygenase inhibition, but was blocked by luminal administration of the small and intermediate conductance Ca2+-activated K+ channel blockers apamin and TRAM34. BaCl2, a blocker of inwardly rectifying K+ (KIR) channels, also inhibited AITC-induced dilation. AITC-induced smooth muscle cell hyperpolarization was blocked by apamin and TRAM34. We conclude that Ca2+ influx via endothelial TRPA1 channels elicits vasodilation of cerebral arteries by a mechanism involving endothelial cell Ca2+- activated K+ channels and KIR channels in arterial myocytes.