Induction of hypertension and peripheral inflammation by deletion of extracellular superoxide dismutase in the central nervous system

Abstract

Superoxide has been implicated in central neural control of blood pressure. The circumventricular organs (CVO) lack a well‐formed blood‐brain barrier and produce superoxide (O2·‐) in response to angiotensin II and other hypertensive stimuli. The extracellular superoxide dismutase (SOD3) is expressed in cells associated with the CVO. To understand the role of SOD3 in the CVO in blood pressure regulation, we injected an adenovirus encoding Cre‐recombinase (AdCre, 5x108 particles/ml) intracerebroventricularly (ICV) in mice with loxP sites flanking the SOD3 coding region. Deletion of CVO SOD3 increased baseline blood pressure modestly and markedly augmented the hypertensive response to low‐dose angiotensin II (140 ng/kg/day). Deletion of CVO SOD3 also 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. These findings provide insight into how central signals produce vascular inflammation in response to hypertensive stimuli such as angiotensin II. Funded by NIH R01 HL39006 and PPG HL58000.