Induction of hypertension and peripheral inflammation by reduction of extracellular superoxide dismutase in the central nervous system.
Induction of hypertension and peripheral inflammation by reduction of extracellular superoxide dismutase in the central nervous system.
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DOI：
10.1161/hypertensionaha.109.142646
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发表时间：
2010-02
期刊：
影响因子：
--
通讯作者：
Harrison DG
中科院分区：
文献类型：
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作者：
Lob HE;Marvar PJ;Guzik TJ;Sharma S;McCann LA;Weyand C;Gordon FJ;Harrison DG
室周器官 (CVO) 缺乏结构良好的血脑屏障，并会产生超氧化物 (O2•−) 以响应血管紧张素 II 和其他高血压刺激。中枢 O2•− 的增加与血压调节有关。细胞外超氧化物歧化酶 (SOD3) 在与 CVO 相关的细胞中高度表达，特别是在该区域内的单胞细胞中。为了了解 CVO 中 SOD3 在血压调节中的作用，我们对 SOD3 编码区两侧具有 loxP 位点的小鼠（SOD3loxp/loxp 小鼠）进行侧脑室内（ICV）注射编码 Cre 重组酶的腺病毒（AdCre，5×108 颗粒/ml）。注射编码红色荧光蛋白（AdRFP）的腺病毒作为对照。 CVO SOD3 的缺失会适度增加基线血压，并显着增强对低剂量血管紧张素 II（140 ng/kg/天）的高血压反应，而 ICV 注射 AdRFP 对这些参数的影响很小。 AdCre 治疗的小鼠表现出交感神经对心率和血压变异性的调节增强、血管超氧化物产生增加和 T 细胞活化，其特征是循环 CD69+/CD3+ 细胞增加。 CVO SOD3 的缺失也显着增加了血管紧张素 II 引起的血管 T 细胞和白细胞浸润。我们得出的结论是，CVO 中的 SOD3 在血压调节中发挥着关键作用，其缺失可部分通过调节交感神经流出促进 T 细胞活化和血管炎症。这些发现让我们深入了解中枢信号如何响应血管紧张素 II 等高血压刺激而产生血管炎症。
The circumventricular organs (CVO) lack a well-formed blood-brain barrier and produce superoxide (O2•−) in response to angiotensin II and other hypertensive stimuli. This increase in central O2•− has been implicated in regulation of blood pressure. The extracellular superoxide dismutase (SOD3) is highly expressed in cells associated with CVO, and particularly with tanycytes lining this region. To understand the role of SOD3 in the CVO in blood pressure regulation, we performed intracerebroventricular (ICV) injection an adenovirus encoding Cre-recombinase (AdCre, 5×108 particles/ml) in mice with loxP sites flanking the SOD3 coding region (SOD3loxp/loxp mice). An adenovirus encoding red-fluorescent protein (AdRFP) was injected as a control. Deletion of CVO SOD3 increased baseline blood pressure modestly and markedly augmented the hypertensive response to low-dose angiotensin II (140 ng/kg/day), while ICV injection of AdRFP had minimal effects on these parameters. AdCre treated mice exhibited increased sympathetic modulation of heart rate and blood pressure variability, increased vascular superoxide production and T cell activation as characterized by increased circulating CD69+/CD3+ cells. Deletion of CVO SOD3 also markedly increased vascular T cell and leukocyte infiltration caused by angiotensin II. We conclude that SOD3 in the CVO plays a critical role in regulation of blood pressure and its loss promotes T cell activation and vascular inflammation, in part by modulating sympathetic outflow. These findings provide insight into how central signals produce vascular inflammation in response to hypertensive stimuli such as angiotensin II.