Nishijima Yoshinori, Zheng Xiaodong, Lund Hayley, Suzuki Makoto, Mattson David L, Zhang David X
Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin ; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
Physiol Rep. 2014 Jan 13;2(1):e00199. doi: 10.1002/phy2.199. eCollection 2014 Jan 1.
Transient receptor potential vanilloid type 4 (TRPV4) is an endothelial Ca(2+) 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 Ca(2+) 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.
瞬时受体电位香草酸亚型4（TRPV4）是一种内皮细胞钙内流通道，有助于在传导动脉和阻力动脉中实现内皮介导的血管舒张。我们研究了TRPV4在高血压条件下对血压调节和内皮功能的作用。给TRPV4基因敲除（TRPV4(-/-)）小鼠和野生型（WT）对照小鼠饮用含l-NAME（0.5 g/L）的水7天，或皮下注射血管紧张素（Ang）II（每分钟600 ng/kg）14天，并用无线电遥测法测量血压。TRPV4(-/-)小鼠的基线平均动脉压（MAP）较低（12小时白天MAP，WT对照为99±2 mmHg，TRPV4(-/-)为94±2 mmHg）。与WT对照（6±2%）相比，l-NAME处理使TRPV4(-/-)小鼠的MAP升高幅度略大（第7天，13±4%），但Ang II诱导的MAP升高在TRPV4(-/-)小鼠和WT小鼠中相似（第14天，分别为53±6%和37±11%，P<0.05）。对WT小鼠长期输注Ang II可降低乙酰胆碱（ACh）诱导的血管舒张（对10(-5) mol/L ACh的舒张，为对照的71±5% vs. 92±2%）以及TRPV4激动剂GSK1016790A诱导的小肠系膜动脉舒张（10(-8) mol/L GSK1016790A，为对照的14±5% vs. 77±7%）。然而，Ang II处理对TRPV4(-/-)小鼠的ACh舒张无影响。从机制上讲，Ang II既未显著改变肠系膜动脉中TRPV4的总蛋白表达，也未改变原位肠系膜内皮细胞中TRPV4激动剂诱导的钙反应。这些结果表明，TRPV4通道在l-NAME诱导而非Ang II诱导的高血压中对血压调节起次要作用，但可能在Ang II诱导的内皮功能障碍中起重要作用。
