P47phox-dependent NADPH oxidase regulates flow-induced vascular remodeling
P47phox-dependent NADPH oxidase regulates flow-induced vascular remodeling
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DOI：
10.1161/01.res.0000181759.63239.21
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发表时间：
2005-09-16
影响因子：
20.1
通讯作者：
Lehoux, S
中科院分区：
文献类型：
--
作者：
Castier, Y;Brandes, RP;Lehoux, S
血流的慢性改变引发了一种适应性反应，这种反应倾向于使剪切应力正常化，包括一氧化氮（NO）和基质金属蛋白酶（MMPs）。为了评估NADPH氧化酶在这一过程中的作用，我们建立了连接右颈总动脉（RCCA）和颈静脉的小鼠动静脉瘘（AVF）新模型，该模型不影响血压。采用NADPH缺乏gp91phox和p47phox亚基的小鼠和野生型对照。AVF显著增加RCCA血流量（0.78 +/- 0.12 ~ 4.71 +/- 0.78 mL/min, P < 0.01），导致剪应力突然升高（35 +/- 1 ~ 261 +/- 17 dynes/cm） (2)；P < 0.01)。AVF后1周和3周RCCA直径（460 +/- 14 mu m）逐渐增大（534 +/- 14 mu m和627 +/- 19 mu m， P < 0.01），剪应力降低（173 +/- 13和106 +/- 10 dynes/cm(2)）。在gp91phox（-/-）小鼠中，RCCA口径和剪切应力的变化与对照组相匹配。然而，p47phox（-/-）小鼠RCCAs仅略微增大，因此剪切应力仍然很高（3周时199 +/- 8 dynes/m(2)）。同样，内皮NO合酶（-/-）小鼠的重塑最小。在对照组和gp91phox（-/-）小鼠中，AVF增强了活性氧（ROS）的产生和MMP的诱导，而在p47phox（-/-）和eNOS（-/-）小鼠中，这种反应可以忽略不计。同样，与p47phox（-/-）和eNOS（-/-）小鼠相比，对照和gp91phox（-/-）小鼠的硝基酪氨酸染色表明过氧亚硝酸盐的形成更为明显。因此，剪切应力诱导血管NADPH氧化酶包括p47phox而不包括gp91phox。生成的ROS与NO相互作用产生过氧亚硝酸盐，从而激活MMPs，促进血管重塑。我们的研究首次证明活性氧在血流诱导的血管扩张中起着重要作用。
Chronic alterations in blood flow elicit an adaptive response that tends to normalize shear stress, involving nitric oxide (NO) and matrix metalloproteinases (MMPs). To evaluate the role of NADPH oxidase in this process, we developed a new model of mouse arteriovenous fistula (AVF) connecting the right common carotid artery (RCCA) with the jugular vein, which does not affect blood pressure. Mice deficient for gp91phox and p47phox subunits of NADPH and wild-type controls were used. AVF greatly increased RCCA blood flow (0.78 +/- 0.12 to 4.71 +/- 0.78 mL/min; P < 0.01), producing an abrupt rise in shear stress (35 +/- 1 to 261 +/- 17 dynes/cm(2); P < 0.01) within 24 hours. RCCA diameter (460 +/- 14 mu m) gradually enlarged 1 and 3 weeks after AVF (534 +/- 14 mu m and 627 +/- 19 mu m; P < 0.01), reducing shear stress (173 +/- 13 and 106 +/- 10 dynes/cm(2), respectively). In gp91phox (-/-) mice, changes in RCCA caliber and shear stress matched controls. However, p47phox (-/-) mouse RCCAs enlarged only marginally, such that shear stress remained high (199 +/- 8 dynes/m(2) at 3 weeks). Likewise, remodeling was minimal in endothelial NO synthase (eNOS) (-/-) mice. In both control and gp91phox (-/-) animals, reactive oxygen species (ROS) production and MMP induction was enhanced by AVF, whereas in p47phox (-/-) and eNOS (-/-) mice such response was negligible. Similarly, nitrotyrosine staining, indicating peroxynitrite formation, was more pronounced in control and gp91phox (-/-) mice than in p47phox (-/-) and eNOS (-/-) mice. Hence, shear stress induces vascular NADPH oxidase comprising p47phox but not gp91phox. Generated ROS interact with NO to produce peroxynitrite, which in turn activates MMPs, facilitating vessel remodeling. Our study provides the first evidence that ROS play a fundamental role in flow- induced vascular enlargement.