Induction of Hypertension and Peripheral Inflammation by Reduction of Extracellular Superoxide Dismutase in the Central Nervous System

• Type of Material: Article
• Authors: Heinrich E. Lob, Emory University; Paul J. Marvar, Emory University; Tomasz J. Guzik, Emory University; Shraya Sharma, Emory University; Louise A. McCann, Emory University; Cornelia Weyand, Emory University; Frank J Gordon, Emory University; David G Harrison, Emory University
• Language: English
• Date: 2010-02
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 American Heart Association, Inc. All rights reserved.
• Final Published Version (URL): http://hyper.ahajournals.org/content/55/2/277
• Title of Journal or Parent Work: Hypertension
• ISSN: 0194-911X
• Volume: 55
• Issue: 2
• Grant/Funding Information: This work was supported by NIH Grants P01HL58000, R01HL39006, P01HL58000 and a VA Merit Grant. Heinrich E. Lob is supported through an American Heart Association Postdoctoral Fellowship Grant 0825345E.
• Keywords: T cell; circumventricular organ; Superoxide dismutase; hypertension
• Research Categories: Health Sciences, Immunology

Abstract

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.