An acute rise in intraluminal pressure shifts the mediator of flow-mediated dilation from nitric oxide to hydrogen peroxide in human arterioles
An acute rise in intraluminal pressure shifts the mediator of flow-mediated dilation from nitric oxide to hydrogen peroxide in human arterioles
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DOI：
10.1152/ajpheart.00557.2014
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发表时间：
2014-12-01
影响因子：
4.8
通讯作者：
Gutterman, David D.
中科院分区：
文献类型：
--
作者：
Beyer, Andreas M.;Durand, Matthew J.;Gutterman, David D.
内皮型一氧化氮（NO）是人体脂肪微血管血流介导扩张（FMD）的主要介质。急性和慢性高血压后，NO介导的血管舒张功能受损，可能是由于活性氧（ROS）的过量产生。压力升高在人体小动脉扩张受损中的直接作用尚不清楚。我们检验了压力升高足以损害FMD的假设。从人脂肪组织中分离小动脉并插管，在暴露于增加的管腔内压力（IILP; 150 mmHg，30 min）之前和之后测量血管舒张至分级流量梯度。使用药理学试剂来确定FMD的介体以减少NO [N-G-硝基-L-精氨酸甲酯（L-NAME）、2-（4-羧基苯基）-4，4，5，5-四甲基咪唑啉-1-氧基-3-氧化物（c-PTIO）]或H2 O2 [聚乙二醇（PEG）-过氧化氢酶]，并且使用荧光显微镜来定量线粒体（mt）ROS。暴露于IILP降低了总体FMD（最大%扩张：82.7 +/- 4.9对比62 +/- 5.6; P < 0.05）。在IILP后用L-NAME预压和PEG-过氧化氢酶处理消除了这种扩张（最大扩张%：L-NAME：23.8 +/- 6.1 vs. 74.8 +/- 8.6; PEG-过氧化氢酶：71.8 +/- 5.9 vs. 24.6 +/- 10.6）。为了检查这种变化是否由mtROS介导，在复合物I抑制剂鱼藤酮或线粒体抗氧化剂mitoTempol存在下测量FMD反应。IILP前，FMD不受任何化合物的影响;然而，IILP后两者均抑制扩张。线粒体过氧黄1（MitoPY 1）的荧光强度，一种H2 O2的线粒体特异性荧光探针，在IILP后的流动过程中增加（相对于静态的%变化：12.3 +/- 14.5 vs. 127.9 +/- 57.7）。这些结果证明了一种新的补偿性扩张机制，在人类中，这是由IILP触发，诱导FMD的介质从NO的变化，以水衍生的H2 O2。
Endothelial nitric oxide (NO) is the primary mediator of flow-mediated dilation (FMD) in human adipose microvessels. Impaired NO-mediated vasodilation occurs after acute and chronic hypertension, possibly due to excess generation of reactive oxygen species (ROS). The direct role of pressure elevation in this impairment of human arteriolar dilation is not known. We tested the hypothesis that elevation in pressure is sufficient to impair FMD. Arterioles were isolated from human adipose tissue and cannulated, and vasodilation to graded flow gradients was measured before and after exposure to increased intraluminal pressure (IILP; 150 mmHg, 30 min). The mediator of FMD was determined using pharmacological agents to reduce NO [N-G-nitro-L-arginine methyl ester (L-NAME), 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO)], or H2O2 [polyethylene glycol (PEG)-catalase], and mitochondrial (mt) ROS was quantified using fluorescence microscopy. Exposure to IILP decreased overall FMD (max %dilation: 82.7 +/- 4.9 vs. 62 +/- 5.6; P < 0.05). This dilation was abolished by treatment with L-NAME prepressure and PEG-catalase after IILP (max % dilation: L-NAME: 23.8 +/- 6.1 vs. 74.8 +/- 8.6; PEG-catalase: 71.8 +/- 5.9 vs. 24.6 +/- 10.6). To examine if this change was mediated by mtROS, FMD responses were measured in the presence of the complex I inhibitor rotenone or the mitochondrial antioxidant mitoTempol. Before IILP, FMD was unaffected by either compound; however, both inhibited dilation after IILP. The fluorescence intensity of mitochondria peroxy yellow 1 (MitoPY1), a mitochondria-specific fluorescent probe for H2O2, increased during flow after IILP (% change from static: 12.3 +/- 14.5 vs. 127.9 +/- 57.7). These results demonstrate a novel compensatory dilator mechanism in humans that is triggered by IILP, inducing a change in the mediator of FMD from NO to mitochondria-derived H2O2.