Psychological trauma increases blood pressure sensitivity to angiotensin II via T-lymphocytes independent of psychopathology

Abstract

Exposure to traumatic stress can lead to psychopathology, including post-traumatic stress disorder (PTSD), but may also cause inflammation and cardiovascular dysfunction. Clinical evidence suggests that exposure to traumatic stress, independent of psychopathology development, may be sufficient to induce pathophysiological sequelae, but this has not been thoroughly investigated. Using a model of repeated social defeat stress (RSDS), we explored links between the behavioral and physiological consequences of this paradigm. RSDS was sufficiently able to elevate systemic inflammation in both male and female mice, with no observed sex differences. RSDS also induced a heightened blood pressure sensitization response to low dose exogenous angiotensin II (AngII), suggesting the model was also sufficient in generating cardiovascular pathology. Interestingly, the RSDS-induced sensitization to AngII was completely abrogated in mice lacking T-lymphocytes (i.e., Rag2^-/- mice). Of note, Rag2^-/- mice demonstrated similar pro-social and anxiety-like behavior to wild-type mice, inferring that 1) differences in these behavioral outcomes do not explain the loss of RSDS-induced AngII sensitization in Rag2^-/- mice and 2) T-lymphocytes do not appear to impact these specific RSDS-induced behaviors. Indeed, intra-animal correlations demonstrate a tight association between the inflammatory and cardiovascular consequences post-RSDS, but no associations between these parameters with behavior. Together, our data suggest that exposure to traumatic stress, independent of psychopathology, is sufficient to induce pathophysiology. These findings have significant clinical implications, specifically for individuals who have experienced traumatic stress without the development of psychopathology, as this overlooked population may have similar risks of developing somatic diseases.

Keywords: Behavior; Interleukin 17A; Repeated Social Defeat Stress; Stress; Tcells.

Figure 1.. T-lymphocytes do not impact pro-social or anxiety-like behavior.

RSDS was induced in male and female wild-type (WT) and Rag2^−/− mice followed by the assessment of pro-social behavior by the social interaction test and anxiety-like behavior by the elevated zero maze. A. Total distance moved on the elevated zero maze for WT mice. B. Time spent in the open arms of the elevated zero maze for WT mice. C. Social interaction (SI) ratio of WT mice in the social interaction test. D. Total distance moved on the elevated zero maze for Rag2^−/− mice. E. Time spent in the open arms of the elevated zero maze for Rag2^−/− mice. F. Social interaction (SI) ratio of Rag2^−/− mice in the social interaction test. Statistics by 2-way ANOVA with Bonferroni post-hoc.

Figure 2.. RSDS sensitizes mice to AngII via T-lymphocytes.

RSDS was induced in male and female wild-type (WT) and Rag2^−/− mice with implanted radiotelemetry transmitters, and mean arterial pressure (MAP) was assessed daily throughout the duration of the experiment. A. MAP over time for the duration of the experimental paradigm in WT mice. B. Quantification of maximum blood pressure change from baseline to maximum level during AngII infusion in WT and Rag2^−/− mice. No sex differences were noted between males and females, so data are shown as pooled. Statistics by 2-way ANOVA with Bonferroni post-hoc.

Figure 3.. IL-17A is elevated after RSDS, but not in Rag2^−/− mice.

RSDS was induced in male and female wild-type (WT) and Rag2^−/− mice followed by the extraction of peripheral blood and plasma isolation. A. IL-17A levels assessed by Mesoscale Discovery assay in WT and Rag2^−/− mice. Males and females pooled among genotypes. B. IL-17A levels assessed by Mesoscale Discovery assay in WT male and female animals. Statistics by 2-way ANOVA with Bonferroni post-hoc.

Figure 4.. AngII sensitization is linked to IL-17A, but not behavior after RSDS.

RSDS was induced in male and female wild-type (WT) with implanted radiotelemetry followed by the assessment of behavior and circulating IL-17A levels. A. Correlation between IL-17A and maximum mean arterial pressure (MAP) after AngII infusion. B. Correlation between social interaction (SI) ratio and maximum mean arterial pressure (MAP) after AngII infusion. C. Correlation between time spent in the open arms of the elevated zero maze and maximum mean arterial pressure (MAP) after AngII infusion. Males and females pooled. Statistics by Pearson correlation analysis.