T lymphocytes and vascular inflammation contribute to stress-dependent hypertension

Abstract

Background: Psychological stress is a significant risk factor for hypertension and also directly affects the immune system. We have previously reported that T lymphocytes are essential for development of hypertension and that the central nervous system contributes to peripheral T-lymphocyte activation and vascular inflammation in this disease; however, the role of T-cell activation in stress-related hypertension remains unclear.

Methods: Wild-type and T-cell-deficient (RAG-1(-/-)) mice were subjected to daily episodes of stress and blood pressure was measured. Circulating T-cell activation markers and vascular infiltration of immune cells were analyzed, as were stress hormone levels and gene expression changes in the brain. The effects angiotensin II infusion in the presence of chronic stress was also studied.

Results: Repeated daily stress contributed to acute elevations in blood pressure that were associated with increased activation of circulating T cells and increased vascular infiltration of T cells. Repeated stress increased blood pressure in wild-type but not RAG-1(-/-) mice. Adoptive transfer of T cells to RAG-1(-/-) mice restored blood pressure elevation in response to stress. Stress-related hypertension and vascular infiltration of T cells was markedly enhanced by angiotensin II. Moreover, angiotensin II-infused mice exposed to chronic stress exhibited greater blood pressure reactivity to an episode of acute stress.

Conclusions: These data demonstrate that stress-dependent hypertension triggers an inflammatory response that raises blood pressure at baseline and augments the hypertension caused by angiotensin II. These data provide insight as to how psychological stress contributes to hypertension.

Figure 1. Effect of chronic stress on neurohormonal and behavioral measures

Panel A: Percent time in open arms of elevated plus maze test of stress (n=16) and control (n=12) groups. Plasma corticosterone in stress (n=19) and control (n=15) groups. Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus (PVN) of stress (n=8) and control (n=9) groups (Panel C). Panel D depicts a coronal brain section with a dashed line surrounding the region of the PVN isolated for RT-qPCR. (*P<0.05).

Figure 2. Effect of chronic stress on blood pressure, T cell activation and vascular infiltration

Panel A: Blood pressure at baseline and following 7 days of stress (n=18) or control no stress (n=15). Representative histograms (Panel B) and mean data (Panel C) of percentage of circulating CD4+ lymphocytes expressing the early activation marker CD69 and tissue homing marker CD44 for stressed and control mice. Total CD3+ T cells (Panel D) in aortas of stressed (n=15) and control (n=11) mice. (*P<0.05) (Dashed Line represents stress; Solid Line no stress control).

Figure 3. Effect of chronic stress on blood pressure and neurohormonal and behavioral measures in RAG1^−/− mice

Panel A: Blood pressure measured by tail cuff at baseline and following 7 days of stress. WT control and WT + stress (n=5); RAG1^−/− + stress (n=8) or RAG1^−/− + T-cells + stress (n=5). Percent time in open arms of elevated plus maze test of WT (n=18–20) and RAG1^−/− (n=17–20) groups (Panel C). Plasma corticosterone measurements in WT (n=28) and RAG1^−/− (n=25) groups (Panel D). Corticotropin releasing hormone mRNA gene expression in the PVN of WT (n=11–12) and RAG1^−/− (n=10–12) groups (Panel E). (WT+ stress vs WT *P<0.05) (RAG1^−/− + T cell + stress vs RAG1^−/− + stress **P<0.05).

Figure 4. Effect of acute and chronic stress following 7 days of low-dose angiotensin II infusion on blood pressure

Panel A: Blood pressure at baseline and following 14 days of angiotensin II infusion and 7 days of repeated stress. Ang II + stress (n=16);Ang II (n=12); Vehicle + stress (n=13) or Vehicle (n=10). Diurnal blood pressure for Vehicle + stress (n=7) or Vehicle (n=3) and Ang II + stress (n=9);Ang II (n=7) (Panel B–C). Following seven days of daily stress, acute blood pressure response to cage switch stress (n=8–10) (Panel D). (*P<0.05 Vehicle vs Vehicle + stress; **P<0.05 Ang II vs Ang II + stress; †P<0.05 Ang II vs Vehicle).

Figure 5. Effect of chronic stress on T cell activation and vascular infiltration following low-dose angiotensin II

Percentage of circulating CD4+ lymphocytes expressing the early activation marker CD69 and tissue homing marker CD44 (Panels A–B) for stressed and control Ang II and vehicle mice (n=11–16). Total number of CD45+ leukocytes (Panel C) and CD3+ T cells (Panel D) in aortas of stressed and control Ang II and vehicle mice (n=10–13). (*P<0.01 Ang II vs Ang + Stress).

Figure 6. Effect of chronic stress following 7 days of low-dose angiotensin II infusion on neurohormonal and behavioral measures

Panel A: Percent time in open arms of elevated plus maze test of vehicle (n=16–18) and Ang II (n=17–19) groups. Plasma corticosterone in vehicle (n=16–17) and Ang II (n=18–20) groups (Panel B). Corticotropin releasing hormone mRNA levels in the PVN of vehicle (n=6) and Ang II (n=7) groups (Panel C). (**P<0.05 Vehicle control vs Ang II) (*P<0.05 Control vs Stress) (†P<0.05 Vehicle + stress vs Ang II + stress).