Cerebral Arteriogenesis is Enhanced by Pharmacological as Well as Fluid-Shear-Stress Activation of the Trpv4 Calcium Channel
Cerebral Arteriogenesis is Enhanced by Pharmacological as Well as Fluid-Shear-Stress Activation of the Trpv4 Calcium Channel
复制标题
DOI：
10.1016/j.ejvs.2010.11.034
复制
发表时间：
2011-05-01
影响因子：
5.7
通讯作者：
Schmitz-Rixen, T.
中科院分区：
文献类型：
--
作者：
Schierling, W.;Troidi, K.;Schmitz-Rixen, T.
目的：本研究旨在确定对剪切应力敏感的钙通道Trpc1、Trpm7、Trpp2、Trpv2（瞬时受体电位阳离子通道V亚族成员2）和Trpv4对脑动脉生成的重要性。分析了表达谱，比较了靶向药物对侧支生长的刺激与最大程度增加的流体剪切应力（FSS）所实现的刺激。
设计：一项前瞻性对照研究，其中大鼠接受双侧颈动脉结扎（BCL），或BCL +动静脉瘘，或BCL +药物应用。
方法：通过定量实时聚合酶链反应（qRT - PCR）和免疫组织化学测定FSS刺激的脑侧支中的信使RNA（mRNA）丰度和蛋白质表达。通过渗透微型泵应用药物，并通过死后血管造影和Ki67免疫染色评估动脉生成。
结果：Trpv4是唯一在FSS刺激后mRNA丰度和蛋白质表达显著增加的机械敏感型Trp通道。与对照组（长度：3.80 ± 0.06毫米，直径：237.3 ± 5.3微米）相比，4α - 佛波醇 - 12,13 - 二癸酸酯对Trpv4的激活导致侧支生长显著增强（长度：4.43 ± 0.20毫米，直径：282.6 ± 8.1微米）。药物应用对动脉生成的刺激程度几乎与最大FSS刺激相同（长度：4.61 ± 0.07毫米，直径：327.4 ± 12.6微米）。
结论：Trpv4在FSS刺激的脑侧支中表达显著增加。Trpv4的药理学激活增强了脑动脉生成，表明Trpv4可能是开发新治疗概念的候选者。（C）2010欧洲血管外科学会。由爱思唯尔有限公司出版。保留所有权利。
Objectives: This study aimed to determine the importance of the shear-stress-sensitive calcium channels Trpc1, Trpm7, Trpp2, Trpv2 (transient receptor potential cation channel, subfamily V, member 2) and Trpv4 for cerebral arteriogenesis. The expression profiles were analysed, comparing the stimulation of collateral growth by target-specific drugs to that achieved by maximum increased fluid shear stress (FSS).Design: A prospective, controlled study wherein rats were subjected to bilateral carotid artery ligature (BCL), or BCL + arteriovenous fistula, or BCL + drug application.Methods: Messenger RNA (mRNA) abundance and protein expression were determined in FSS-stimulated cerebral collaterals by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry. Drugs were applied via osmotic mini pumps and arteriogenesis was evaluated by post-mortem angiograms and Ki67 immunostaining.Results: Trpv4 was the only mechanosensitive Trp channel showing significantly increased mRNA abundance and protein expression after FSS stimulation. Activation of Trpv4 by 4 alpha-phorbol-12,13-didecanoate caused significantly enhanced collateral growth (length: 4.43 +/- + 0.20 mm and diameter: 282.6 +/- 8.1 mu m) compared with control (length: 3.80 +/- 0.06 mm and diameter: 237.3 +/- 5.3 mu m). Drug application stimulated arteriogenesis to almost the same extent as did maximum FSS stimulation (length: 4.61 +/- 0.07 mm and diameter: 327.4 +/- 12.6 mu m).Conclusions: Trpv4 showed significantly increased expression in FSS-stimulated cerebral collaterals. Pharmacological Trpv4 activation enhanced cerebral arteriogenesis, pinpointing Trpv4 as a possible candidate for the development of new therapeutic concepts. (C) 2010 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.