TRPV4 (Transient Receptor Potential Vanilloid 4) Mediates Endothelium-Dependent Contractions in the Aortae of Hypertensive Mice
TRPV4 (Transient Receptor Potential Vanilloid 4) Mediates Endothelium-Dependent Contractions in the Aortae of Hypertensive Mice
复制标题
TRPV4（瞬时受体电位香草酸 4）介导高血压小鼠主动脉内皮依赖性收缩
DOI：
10.1161/hypertensionaha.117.09767
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发表时间：
--
期刊：
影响因子：
8.3
通讯作者：
Ma X
中科院分区：
文献类型：
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作者：
Zhang P;Sun C;Li H;Tang C;Kan H;Yang Z;Mao A;Ma X
TRPV 4（瞬时受体电位香草酸4）在调节高血压小鼠血管收缩中的作用尚不明确。我们检验了TRPV 4通过激活胞浆cPLA 2（磷脂酶A2）和COX 2（环氧合酶2）调节高血压小鼠动脉粥样硬化中内皮依赖性收缩的假设，并鉴定了COX 2产生的可能的内皮源性收缩因子。使用肌电图，我们证明了GSK 1016790 A（TRPV 4激动剂）和乙酰胆碱（ACh）触发高血压小鼠动脉内皮依赖性收缩，TRPV 4缺失时收缩被消除。PLA 2测定和Western blotting结果显示，盐性高血压大鼠cPLA 2活性升高，HC 067047或Ca ~（2+）螯合剂可抑制cPLA 2活性。TRPV 4和ACh引起的收缩可被cPLA 2抑制剂或细胞外Ca ~（2+）清除所抑制。高血压小鼠内皮细胞COX 2表达增强，COX 2抑制剂可抑制TRPV 4或ACh诱导的收缩。酶免疫分析显示，高血压小鼠前列腺素F2α（PGF 2 α）的释放增加。GSK 1016790 A或ACh可触发PGF 2 α的释放，cPLA 2抑制剂HC 067047和COX 2抑制剂可抑制PGF 2 α的释放。S18886可显著降低GSK 1016790 A、ACh和PGF 2 α诱导的盐性高血压小鼠收缩。目前的研究表明，在高血压小鼠中，由COX 2在内皮中产生的PGF 2 α是最可能的内皮源性收缩因子，其基础是内皮依赖性的、TRPV 4介导的收缩。这种收缩涉及细胞内Ca 2+浓度和cPLA 2活性的增加。这些结果提示TRPV 4在高血压小鼠血管内皮依赖性收缩中起重要作用。
The role of TRPV4 (transient receptor potential vanilloid 4) in regulating vascular contraction in hypertensive mice is poorly established. We tested the hypothesis that TRPV4 regulates endothelium-dependent contractions in aortas from hypertensive mice through the activation of cytosolic cPLA2(phospholipase A2) and COX2 (cyclooxygenase 2) and identified the possible endothelium-derived contracting factor generated by COX2. Using myography, we demonstrated that GSK1016790A (a TRPV4 agonist) and acetylcholine (ACh) trigger endothelium-dependent contractions in aortas from hypertensive mice, and the contractions were abolished with TRPV4 deletion. PLA2assay and Western blotting showed that cPLA2activity was higher in salt-induced hypertension and HC067047 or a Ca2+chelator inhibited cPLA2activity. Contractions induced by TRPV4 and ACh were inhibited by the cPLA2inhibitor or removal of extracellular Ca2+. COX2 expression was enhanced in the endothelium from hypertensive mice and contractions induced by TRPV4 or ACh were inhibited by the COX2 inhibitor. Enzyme immunoassay showed that the release of prostaglandin F2α(PGF2α) was increased in hypertensive mice. GSK1016790A or ACh triggered the release of PGF2αand this was inhibited by HC067047, the cPLA2inhibitor, and COX2 inhibitor. GSK1016790A, ACh, and PGF2αinduced contractions were significantly reduced by S18886 in salt-induced hypertensive mice. The present study demonstrates that PGF2αgenerated by COX2 in the endothelium is the most likely endothelium-derived contracting factor underlying endothelium-dependent, TRPV4-mediated contraction in hypertensive mice. This contraction involved increased intracellular Ca2+concentrations and cPLA2activity. These results suggested an important role of TRPV4 in endothelium-dependent contraction in mice during hypertension.