Characterization of blood pressure and endothelial function in TRPV4-deficient mice with l-NAME- and angiotensin II-induced hypertension.
Characterization of blood pressure and endothelial function in TRPV4-deficient mice with l-NAME- and angiotensin II-induced hypertension.
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DOI：
10.1002/phy2.199
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发表时间：
2014-01-01
影响因子：
2.5
通讯作者：
Zhang, David X
中科院分区：
文献类型：
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作者：
Nishijima, Yoshinori;Zheng, Xiaodong;Lund, Hayley;Suzuki, Makoto;Mattson, David L;Zhang, David X
瞬时受体电位香草样蛋白4 （TRPV4）是内皮Ca2+进入通道，在导管和阻力动脉中促进内皮介导的扩张。我们研究了TRPV4在高血压条件下调节血压和内皮功能的作用。TRPV4 -缺陷（TRPV4−/−）和野生型（WT）对照小鼠在饮用水中给予l - NAME (0.5 g/ l) 7天或皮下注射血管紧张素（Ang） II （600 ng/kg /分钟）14天，并通过无线电遥测测量血压。TRPV4−/−小鼠的基线平均动脉压（MAP）较低（12小时白天MAP， WT对照组为94±2 mmHg，对照组为99±2 mmHg）。与WT对照组（6±2%）相比，l‐NAME处理诱导TRPV4−/−小鼠的MAP增加略高（第7天，13±4%），但Ang II诱导的TRPV4−/−小鼠和WT小鼠的MAP增加相似（第14天，53±6%和37±11%，P < 0.05）。长期向WT小鼠输注Ang II可降低乙酰胆碱（ACh）诱导的扩张（扩张至10−5 mol/L ACh， 71±5%，对照组为92±2%）和TRPV4激动剂GSK1016790A诱导的肠系膜小动脉扩张（10−8 mol/L GSK1016790A, 14±5%，对照组为77±7%）。然而，Ang II治疗不影响TRPV4−/−小鼠的乙酰胆碱扩张。在机制上，Ang II没有显著改变肠系膜动脉中TRPV4总蛋白表达或TRPV4激动剂诱导的肠系膜内皮细胞原位Ca2+反应。这些结果表明，TRPV4通道在l - NAME患者的血压调节中起次要作用，但在Ang II诱导的高血压中不起作用，但可能在Ang II诱导的内皮功能障碍中起重要作用。我们研究了瞬时受体电位香草样蛋白4 （TRPV4）在正常情况下体内调节血管张力和应对高血压挑战中的作用。我们的研究结果表明，TRPV4通道可能在应激下的血管张力和内皮功能的控制中发挥复杂的作用。
Transient receptor potential vanilloid type 4 (TRPV4) is an endothelial Ca2+ entry channel contributing to endothelium‐mediated dilation in conduit and resistance arteries. We investigated the role of TRPV4 in the regulation of blood pressure and endothelial function under hypertensive conditions. TRPV4‐deficient (TRPV4−/−) and wild‐type (WT) control mice were given l‐NAME (0.5 g/L) in drinking water for 7 days or subcutaneously infused with angiotensin (Ang) II (600 ng/kg per minute) for 14 days, and blood pressure measured by radiotelemetry. TRPV4−/− mice had a lower baseline mean arterial pressure (MAP) (12‐h daytime MAP, 94 ± 2 vs. 99 ± 2 mmHg in WT controls). l‐NAME treatment induced a slightly greater increase in MAP in TRPV4−/− mice (day 7, 13 ± 4%) compared to WT controls (6 ± 2%), but Ang II‐induced increases in MAP were similar in TRPV4−/− and WT mice (day 14, 53 ± 6% and 37 ± 11%, respectively, P < 0.05). Chronic infusion of WT mice with Ang II reduced both acetylcholine (ACh)‐induced dilation (dilation to 10−5 mol/L ACh, 71 ± 5% vs. 92 ± 2% of controls) and the TRPV4 agonist GSK1016790A‐induced dilation of small mesenteric arteries (10−8 mol/L GSK1016790A, 14 ± 5% vs. 77 ± 7% of controls). However, Ang II treatment did not affect ACh dilation in TRPV4−/− mice. Mechanistically, Ang II did not significantly alter either TRPV4 total protein expression in mesenteric arteries or TRPV4 agonist‐induced Ca2+ response in mesenteric endothelial cells in situ. These results suggest that TRPV4 channels play a minor role in blood pressure regulation in l‐NAME‐ but not Ang II‐induced hypertension, but may be importantly involved in Ang II‐induced endothelial dysfunction. We investigated the role of transient receptor potential vanilloid type 4 (TRPV4) in regulating vascular tone in vivo under normal conditions and in response to hypertensive challenges. Our results indicate that TRPV4 channels may play a complex role in the control of vascular tone and endothelial function under stress.