Commentary Angiotensin II , Oxidant Signaling , and Hypertension Down to a T ?

It has been 30 years since landmark studies by Johnson and Brody1 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 al3 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 redox signaling and how it regulates hemodynamics. The second and potentially groundbreaking finding in the study by Lob et al3 is that the SFO, at least in part through SOD3, may couple central and peripheral oxidant systems through activation of peripheral T cells, thereby providing a possible common underlying mechanism of hypertension that spans multiple organ systems. These investigators show that SOD3 ablation in the SFO is sufficient to increase oxidants in both the SFO and the aorta, and this is accompanied by an elevation in sympathetic output and an increase in the number of circulating CD69 T lymphocytes. The addition of lowdose Ang II infusion does not have further effects on these end points in the SOD3-ablated mice. In contrast, it does enhance the number of inflammatory CD45 , CD3 , and CD69 cells and expression of T-cell recruitment molecules in peripheral aortic tissue. Broadly interpreted, these results suggest that elevating extracellular O2 levels in the SFO through deletion of SOD3 causes significant alterations in peripheral T-cell activation and vascular O2 regulation and inflammation, leading to hypertension. As with all potentially important discoveries, this study raises as many questions as it answers. The first and perhaps most important is the sequence of interplay (and, therefore, the exact cause-effect relationships) between the multiple signaling systems invoked, including O2 in the SFO, sympathetic outflow, T-cell activation, vascular O2 regulation, vascular infiltration, and blood pressure. Given the increase in basal sympathetic outflow with SOD3 deletion in SFO and the known effect of oxidant stress to induce sympathoexcitation, it is highly plausible that this is a key initiating mechanism linking the central and peripheral responses observed in this study. Indeed, increased sympathetic activity could lead to each of the responses observed after The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Biomedical Sciences (R.L.D.), College of Veterinary Medicine, Cornell University, Ithaca, N.Y.; Department of Cell and Developmental Biology (R.L.D.), Weill Cornell Medical College, New York, N.Y.; Department of Cellular and Integrative Physiology (M.C.Z.), University of Nebraska Medical Center, Omaha, Nebr. Correspondence to Robin L. Davisson, Departments of Biomedical Sciences (College of Veterinary Medicine) and Cell and Developmental Biology (Weill Cornell Medical College), Cornell University, T9-014 Veterinary Research Tower, Ithaca, NY 14853-6401. E-mail [email protected] (Hypertension. 2010;55:228-230.) © 2010 American Heart Association, Inc.