Increasing TRPV4 expression restores flow-induced dilation impaired in mesenteric arteries with aging.
Increasing TRPV4 expression restores flow-induced dilation impaired in mesenteric arteries with aging.
复制标题
增加 TRPV4 表达可恢复因衰老而受损的肠系膜动脉血流诱导的扩张
DOI：
10.1038/srep22780
复制
发表时间：
2016-03-07
影响因子：
4.6
通讯作者：
Shen B
中科院分区：
文献类型：
--
作者：
Du J;Wang X;Li J;Guo J;Liu L;Yan D;Yang Y;Li Z;Zhu J;Shen B
血流刺激内皮细胞内Ca 2+浓度（[Ca 2 +]i）升高是导致血流诱导血管扩张的重要早期事件。瞬时受体电位香草酸亚型4（TRPV 4）是一种Ca ~（2+）可透过的阳离子通道，可促进血流刺激的[Ca ~（2+）]i升高。为了确定TRPV 4是否参与年龄相关性血流诱导的血管扩张损伤，我们测量了大鼠血管直径和一氧化氮（NO）水平，并进行了Ca 2+成像，免疫印迹和免疫染色测定。结果发现，与青年大鼠相比，老年大鼠肠系膜动脉的流量诱导和TRPV 4激活剂4α-PDD诱导的舒张作用明显减弱。在老年大鼠原代培养的肠系膜动脉内皮细胞（MAECs）中，血流或4α-PDD诱导的[Ca 2 +]i升高也显着降低。免疫印迹和免疫染色结果显示MAECs中TRPV 4表达水平随年龄增加而降低。此外，4α-PDD诱导的NO产生在老化的MAEC中显著减少。与慢病毒GFP处理的老年大鼠相比，慢病毒载体递送TRPV 4增加了老年MAECs中TRPV 4的表达水平，并恢复了老年肠系膜动脉中流量和4α-PDD诱导的血管扩张。我们的结论是，受损的TRPV 4介导的Ca 2+信号导致内皮功能障碍，TRPV 4是一个潜在的目标，为临床治疗与年龄相关的血管系统疾病。
The flow-stimulated intracellular Ca2+ concentration ([Ca2+]i) rise in endothelial cells is an important early event leading to flow-induced blood vessel dilation. Transient receptor potential vanilloid subtype 4 (TRPV4), a Ca2+-permeable cation channel, facilitates the flow-stimulated [Ca2+]i rise. To determine whether TRPV4 is involved in age-related flow-induced blood vessel dilation impairment, we measured blood vessel diameter and nitric oxide (NO) levels and performed Ca2+ imaging, immunoblotting, and immunostaining assays in rats. We found that the flow-induced and TRPV4 activator 4α-PDD-induced dilation of mesenteric arteries from aged rats were significantly decreased compared with those from young rats. The flow- or 4α-PDD-induced [Ca2+]i rise was also markedly reduced in primary cultured mesenteric artery endothelial cells (MAECs) from aged rats. Immunoblotting and immunostaining results showed an age-related decrease of TRPV4 expression levels in MAECs. Additionally, the 4α-PDD-induced NO production was significantly reduced in aged MAECs. Compared with lentiviral GFP-treated aged rats, lentiviral vector delivery of TRPV4 increased TRPV4 expression level in aged MAECs and restored the flow- and 4α-PDD-induced vessel dilation in aged mesenteric arteries. We concluded that impaired TRPV4-mediated Ca2+ signaling causes endothelial dysfunction and that TRPV4 is a potential target for clinical treatment of age-related vascular system diseases.