Turning Dilatation to Constriction: Endothelial TRPV4 (Transient Receptor Potential Vanilloid 4) Matters.
Turning Dilatation to Constriction: Endothelial TRPV4 (Transient Receptor Potential Vanilloid 4) Matters.
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将扩张转变为收缩：内皮 TRPV4（瞬时受体电位香草酸 4）很重要。
DOI：
10.1161/hypertensionaha.117.09848
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发表时间：
2018
期刊：
影响因子：
8.3
通讯作者：
Huang Yu
中科院分区：
文献类型：
--
作者：
Zhu Zhiming;Gao Peng;Huang Yu
Zhu et al TRPV 4在高血压小鼠（而非血压正常小鼠或TRPV 4缺陷小鼠）血管张力57中的双重作用，该作用与cPLA 2（胞浆磷脂酶A2）激活和考克斯-2上调相关;后者增加了前列腺素F2α（PGF 2 α）的产生，前列腺素F2 α是先前在仓鼠血管张力中描述的EDCF之一。2本研究提示，内皮TRPV 4启动的cPLA 2/考克斯-2/PGF 2 α级联反应在高血压时触发内皮依赖性收缩中的重要性。9 Saifeddine等7已经显示了L-NAME（L-NG-硝基精氨酸甲酯）处理的小鼠主动脉的急性内皮依赖性收缩。然而，在Zhang等人的研究中，9 TRPV 4激活剂GSK 1016790 A在基础张力下未引起来自未经L-NAME预孵育的溶媒处理小鼠的平滑肌的任何收缩反应。内皮依赖性收缩仅在诱导高血压后才被发现。Zhang等9和其他人1的结果清楚地表明，内源性NO是生理条件下内皮依赖性收缩的关键负调节剂，高血压中NO的丢失对于内皮依赖性收缩的产生至关重要。然而，NO是否直接减少内皮细胞中COX衍生的EDCF的产生和释放，或者NO是否通过激活鸟苷酸环化酶来松弛VSMC以否定EDCF的作用，仍有待确定。TRPV 4介导的内皮依赖性血管舒张已得到充分证实。高血压疾病如何将TRPV 4的作用转变为血管收缩反应尚待了解。在生理情况下，内皮细胞释放NO以诱导导管动脉响应于钙升高激动剂的舒张，所述钙升高激动剂通常不能诱导内皮依赖性收缩，因为NO是健康动脉中EDCF的有效抑制剂。然而，当血管在高血压中变得发炎时，超氧阴离子的过量产生使内皮细胞中的NO失活并上调考克斯-2以揭示内皮依赖性收缩。10 Zhang et al 9还证实了高盐诱导的高血压小鼠动脉中考克斯-2表达升高，但考克斯-1表达不升高，同时cPLA 2磷酸化增加，考克斯-2抑制剂消除了高血压小鼠动脉中TRPV 4依赖性内皮依赖性收缩（图）。这些新的结果支持早期研究中上调的考克斯-2在内皮功能障碍中的病理作用。1，2，10 EDCFs主要是花生四烯酸的代谢产物。考克斯-1和考克斯-2在高血压的内皮依赖性收缩诱导中起着不可或缺的作用。[1]例如，在自发性高血压大鼠中，NO的产生被一氧化氮合酶抑制剂L-NAME抑制，乙酰胆碱诱导的内皮依赖性收缩被考克斯-1抑制剂抑制。1同时，自发性高血压大鼠肾动脉内皮依赖性收缩主要被考克斯-2抑制剂逆转，10，11表明考克斯-1和考克斯-2在诱导不同血管床内皮依赖性收缩中的不同作用。然而，COX衍生的前列腺素类作为EDCF的类型仍有争议。似乎几种前列腺素类可以作为EDCF，这取决于血管床，物种和病理条件相关的考克斯上调。Zhang et al 9测量并显示PGF 2 α最有可能是负责TRPV 4依赖性EDC的EDCF，从而证实了先前声称的这种前列腺素类在血管内皮依赖性收缩中的作用。
Zhu et al Dual Roles of TRPV4 in Vascular Tone 57 in aortas from hypertensive mice but not from normotensive mice or TRPV4-deficient mice, and this effect was associated with cPLA2 (cytosolic phospholipase A2) activation and COX-2 upregulation; the latter augmented the production of prostaglandin F2α (PGF2α), one of EDCFs previously described in hamster aortas. 2 This study suggests the importance of endothelial TRPV4-initiated cPLA2/COX-2/PGF2α cascade in triggering endothelium-dependent contraction only in hypertension. 9 Saifeddine et al7 have showed an acute endothelium-dependent contraction in L-NAME (L-NG-nitro arginine methyl ester)–treated mouse aorta. However, in the study of Zhang et al, 9 TRPV4 activator GSK1016790A did not cause any contractile response at basal tension in aortas from vehicle-treated mice without L-NAME preincubation. Endothelium-dependent contraction was unmasked only after induction of hypertension. 9 The results from Zhang et al9 and others1 clearly indicate that endogenous NO is a key negative regulator of endothelium-dependent contraction under physiological conditions, and loss of NO in hypertension is critical for generation of endothelium-dependent contraction. However, it remains to be determined whether NO directly reduces the production and release of COX-derived EDCFs in endothelium or NO relaxes VSMCs via activating guanylate cyclase to negate the action of EDCFs. TRPV4-mediated endothelium-dependent vasodilatation is well documented. How a hypertensive condition switches the role of TRPV4 into a vasoconstrictive response is yet to be appreciated. Under physiological situations, endothelial cells release NO to induce relaxations in conduit arteries in response to calcium-elevating agonists that normally cannot induce endothelium-dependent contraction as NO is a potent inhibitor of EDCFs in healthy arteries. However, when blood vessels turn inflamed in hypertension, overproduction of superoxide anions inactivates NO and upregulates COX-2 in endothelial cells to unmask endothelium-dependent contraction. 10 Zhang et al9 also demonstrated elevated expression of COX-2 but not COX-1 together with increased phosphorylation of cPLA2 in aortas from high-salt–induced hypertensive mice, and COX-2 inhibitor abolished TRPV4-dependent endothelium-dependent contraction in hypertensive mouse aortas (Figure). These new results support the pathological role of upregulated COX-2 in endothelial dysfunction in earlier studies. 1, 2, 10EDCFs are primarily the metabolic products of arachidonic acid. Both COX-1 and COX-2 isoforms play indispensable roles in endothelium-dependent contraction induction in hypertension. 1 For example, in aortas from spontaneously hypertensive rats with NO production inhibited by nitric oxide synthase inhibitor L-NAME, acetylcholine-induced endothelium-dependent contraction is inhibited by COX-1 inhibitors. 1 Meanwhile, endothelium-dependent contraction in spontaneously hypertensive rat renal arteries is reversed mainly by COX-2 inhibitors, 10, 11 indicating different roles of COX-1 and COX-2 in inducing endothelium-dependent contraction in different vascular beds. However, the type of COX-derived prostanoids serving as the EDCF remains debated. It seems that several prostanoids can act as EDCFs depending on vascular beds, species, and pathological conditions related to COX upregulation. Zhang et al9 measured and showed that PGF2α is most likely to be the EDCF responsible for TRPV4-dependent EDC, thus confirming the previously claimed role of this prostanoid in endothelium-dependent contraction in …
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影响因子：
8.3
作者：
Liu, Daoyan;Yang, Dachun;Tepel, Martin
通讯作者：
Tepel, Martin
影响因子：
20.1
作者：
Siu Ling Wong;F. Leung;C. Lau;C. Au;L. Yung;X. Yao;Zhen-Yu Chen;P. Vanhoutte;M. Gollasch
通讯作者：
Siu Ling Wong;F. Leung;C. Lau;C. Au;L. Yung;X. Yao;Zhen-Yu Chen;P. Vanhoutte;M. Gollasch
影响因子：
6.6
作者：
X. Tian;W. Wong;F. Leung;Yang Zhang;Yi-xiang Wang;H. Lee;C. Ng;Z. Chen;X. Yao;C. Au
通讯作者：
X. Tian;W. Wong;F. Leung;Yang Zhang;Yi-xiang Wang;H. Lee;C. Ng;Z. Chen;X. Yao;C. Au
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
影响因子：
8.3
作者：
Zhang P;Sun C;Li H;Tang C;Kan H;Yang Z;Mao A;Ma X
通讯作者：
Ma X
影响因子：
29
作者：
Yang D;Luo Z;Ma S;Wong WT;Ma L;Zhong J;He H;Zhao Z;Cao T;Yan Z;Liu D;Arendshorst WJ;Huang Y;Tepel M;Zhu Z
通讯作者：
Zhu Z