Abstract 673: The Central Nervous System Contributes to T-Cell Activation During Angiotensin II-Induced Hypertension
We have recently found that T cells play an important role in angiotensin II (ANG II) induced hypertension. RAG-1−/− mice, which lack both T cells and B cells, have a blunted hypertensive response to ANG II and adoptive transfer of T cells but not B cells restores this response. We have also found that angiotensin II-induced hypertension is associated with a marked increase in T cell infiltration and activation of T cell homing markers. Blood pressure is controlled by central mechanisms, however how T cells might be involved in this remains unclear. We propose that ANG II can act directly on T cells as well as indirectly via increased sympathetic outflow and lead to T cell activation. To test this hypothesis, we produced anteroventral third ventricle (AV3V) brain lesions in mice, which has been previously shown to prevent the central actions of ANG II. AV3V lesions produced adipsia in mice, however this was overcome by training mice to drink water containing 10% sucrose. Following 2 weeks of ANG II infusion, the blood pressure of AV3V lesioned mice was significantly reduced compared to the sham group (AV3V: 122 ± 7.10 mmHg, n = 4; Sham: 170 ± 5.8 mmHg, n = 6). In sham animals, Ang II infusion increased the percent of circulating CD4+ cells expressing the early surface activation marker CD69 and this was significantly blunted by AV3V lesions (9.2 ± 0.56, vs. 6.5 ± 0.71; p = 0.012). The content of αβ CD3 + CD4-CD8- (double negative T cells) in the blood, which have been recently shown to be pro-inflammatory, were also blunted by AV3V lesions (AV3V: 5.2% ± 0.4 Sham: 7.4% ± 0.8, p = 0.03). FACS analysis of single cell suspensions of collagenase digested aortas revealed AV3V lesioning dramatically reduced the total number of leukocytes (CD45 + cells) infiltrating the vessels by 60% (p = 0.035). In summary, following ANG II infusion, lesioning of the AV3V region in mice prevents the increase in blood pressure as well as peripheral T cell activation and aortic T cell infiltration. We conclude that ANG II signaling via the AV3V region leads to T cell activation and promotes vascular infiltration of T cells. These T cells then likely secrete cytokines that stimulate endothelial and vascular smooth muscle NADPH oxidase activity leading to vascular dysfunction.