Angiotensin II, Oxidant Signaling, and Hypertension

Abstract

It has been 30 years since landmark studies by Johnson and Brody 1 revealed a pivotal role for the forebrain circumventricular organs (CVOs) in experimental hypertension. We have since come to understand that these small midline structures, mounted along the cerebral ventricles and lacking well-formed blood-brain barriers, shoulder a huge responsibility for maintaining the delicate balance of cardiovascular and body fluid homeostases. With their exotic cytology and morphology, including “neuron-like” cells lying free on the ependymal surface and unusually dense and complex fenestrated capillary networks, the CVOs are involved in a remarkable array of homeostatic functions ranging from thirst and salt appetite to vasopressin release and sympathetic outflow.2 With the study by Lob et al in this issue of Hypertension, 3 we must also consider adding to this list the key role that CVOs play in linking central and peripheral mechanisms of hypertension through activation of peripheral T lymphocytes. If proven true, these findings could have broad implications for a unifying hypothesis of how the central nervous system, the vasculature, and possibly other peripheral organs, including the kidney, are involved in the etiology of hypertension. The first of 2 major findings in the study by Lob et al 3 supports and extends previous reports that reactive oxygen species signaling in the subfornical organ (SFO), a key forebrain CVO, is critical in angiotensin II (Ang II)–mediated regulation of blood pressure and hypertension. 4,5 Using an established viral gene transfer approach that induces robust transgene expression nearly exclusively in the SFO, 6 Lob et al3 show that SFO-targeted ablation of endogenous extracellular superoxide dismutase (SOD3), 1 of 3 isozymes in mammals that catalyzes dismutation of superoxide (O2 ), causes a significant elevation in basal blood pressure. In addition, deletion of SOD3 in the SFO increases the sensitivity to systemic Ang II at a dose that does not normally affect blood pressure in mice. These studies using gene deletion lead to a similar general conclusion as was made earlier using gene overexpression, namely, that elevated levels of O2 in the SFO lead to hypertension. What is new and important here is the unmasking of a key role for the extracellular form of SOD. In previous studies, we showed that adenoviral-mediated overexpression of cytoplasmic Cu/Zn SOD or mitochondrial SOD but not SOD3 in the SFO interfered with the pressor effects of Ang II. 4,5 However, as shown earlier and reiterated in the study by Lob et al,3 SOD3 is expressed at high basal levels in SFO. This may explain why additional overexpression of this form of the enzyme failed to inhibit the pressor effects of Ang II in our earlier studies. The use of Cre-loxP technology and selective deletion of endogenous SOD3 in the present study elegantly reveal that extracellular O2 signaling in SFO is also important. Future analysis of the relative expression, distribution, and functional role of these 3 SOD isozymes in SFO will be important in understanding the mechanisms of central