Oxidative stress in the central nervous system mediates angiotension II-dependent hypertension

The brain renin-angiotensin system (RAS), of which angiotensin II (AngII) is the primary effector peptide, plays a critical role in the neurohumoral regulation of cardiovascular and body fluid homeostasis by modulating blood pressure, secretion of hypothalamic and pituitary hormones, and water intake. AngII produced locally in the brain or in the systemic circulation can act on brain regions called circumventricular organs (CVO), which lack the blood-brain-barrier. Dysregulation of central AngII signaling is implicated in the pathogenesis of hypertension; therefore, understanding the mechanisms of AngII in the CNS is an important area of investigation. Recently, a novel signaling mechanism for AngII in the periphery has been shown to involve NAD(P)H oxidase-derived reactive oxygen species (ROS). Although ROS are now known to be involved in numerous AngII-regulated processes in peripheral tissues, and are increasingly implicated in CNS neurodegenerative diseases, the role of ROS in central regulation of AngII-induced cardiovascular function remains unexplored. The hypothesis that ROS are critically involved in central AngII signaling and in AngII-dependent blood pressure and drinking behavior was tested by harnessing the power of an array of selective genetic tools, in combination with novel technologies for analysis of cardiovascular function in conscious mice. More specifically, central injections of adenoviruses encoding ROS-modulating molecules were used to examine the redox mechanisms in central AngII-mediated cardiovascular responses in vivo. Neuronal cell cultures were also used to investigate the involvement of NAD(P)H oxidase-derived ROS in AngII signaling, as well as to examine a link between calcium and ROS in intra-neuronal AngII signaling. Finally, in order to better understand the potential role of ROS in the brain in the pathogenesis of AngII-dependent hypertension, a mouse model that recapitulates the characteristics of human hypertension was employed in conjunction with genetic modulation of the redox state of the brain. These studies provide new evidence that ROS are involved in the intracellular signaling mechanism of AngII in the brain under normal and pathological conditions and offer new insight to how dysregulation of redox mechanisms in the brain may lead to the pathogenesis of AngII-dependent hypertension.