Post-traumatic stress disorder (PTSD) is a debilitating psychological disease that increases sympathoexcitation, norepinephrine (NE) outflow, and the risk of cardiovascular diseases like hypertension by >50%, but the mechanisms remain unclear. Hypertension is regulated in part due to immune system-driven inflammation, and our laboratory has previously reported that exposure to NE can modulate levels of T-lymphocyte pro-inflammatory cytokines by redox signaling mechanisms. Therefore, we hypothesized that psychological stress-induced sympathoexcitation leads to a redox-regulated increase in pro-inflammatory cytokine production from T-lymphocytes, which may impact the development of hypertension. Utilizing a mouse-model of PTSD-like psychological stress ( i.e. social defeat), increased sympathoexcitation was confirmed by a 2.5 fold increase in splenic NE content and 4.1 fold increase in tyrosine hydroxylase (TH; p<0.05). Splenic and peripheral T-lymphocytes demonstrated increased reactive oxygen species (ROS) levels as evidenced by enhanced dihydroethidium and MitoSOX Red oxidation (p<0.05). Increases in ROS were correlated with elevated pro-inflammatory cytokines IL-17A, IL-6, and IL-2 in circulation as well as specifically within T-lymphocytes (p<0.05). Examination of hemodynamics elucidated a progressive increase in mean arterial pressure (15 mmHg, p<0.05) over the stress-induction period, correlating with the elevation of T-lymphocyte driven inflammation. This hypertension was not associated with an increase in circulating renin levels. To investigate the causal contribution of T-lymphocytes in driving this hypertension, recombination activating gene 2 (Rag2) knock-out animals, which are devoid of mature lymphocytes, were utilized. Rag2 -/- mice showed no changes in pro-inflammatory cytokines, a 75% decrease in splenic TH levels (p<0.05), and decreased blood pressure after stress, suggesting T-lymphocytes may regulate the stress-induced hypertension. Overall, our data suggest the potential for a new paradigm involving redox control of T-lymphocytes in the regulation of psychological stress-driven hypertension.
