Differential Phenotypes of Tissue-Infiltrating T Cells during Angiotensin II-Induced Hypertension in Mice

Abstract

Hypertension remains the leading risk factor for cardiovascular disease (CVD). Experimental hypertension is associated with increased T cell infiltration into blood pressure-controlling organs, such as the aorta and kidney; importantly in absence of T cells of the adaptive immune system, experimental hypertension is significantly blunted. However, the function and phenotype of these T cell infiltrates remains speculative and undefined in the setting of hypertension. The current study compared T cell-derived cytokine and reactive oxygen species (ROS) production from normotensive and hypertensive mice. Splenic, blood, aortic, kidney and brain T cells were isolated from C57BL/6J mice following 14-day vehicle or angiotensin (Ang) II (0.7 mg/kg/day, s.c.) infusion. T cell infiltration was increased in aorta, kidney and brain from hypertensive mice. Cytokine analysis in stimulated T cells indicated an overall Th1 pro-inflammatory phenotype, but a similar proportion (flow cytometry) and quantity (cytometric bead array) of IFN-γ, TNF-α, IL-4 and IL-17 between vehicle- and Ang II- treated groups. Strikingly, elevated T cell-derived production of a chemokine, chemokine C-C motif ligand 2 (CCL2), was observed in aorta (∼6-fold) and kidney in response to Ang II, but not in brain, spleen or blood. Moreover, T cell-derived ROS production in aorta was elevated ∼3 -fold in Ang II-treated mice (n = 7; P<0.05). Ang II-induced hypertension does not affect the overall T cell cytokine profile, but enhanced T cell-derived ROS production and/or leukocyte recruitment due to elevated CCL2, and this effect may be further amplified with increased infiltration of T cells. We have identified a potential hypertension-specific T cell phenotype that may represent a functional contribution of T cells to the development of hypertension, and likely several other associated vascular disorders.

CXCL12 in Patients with Chronic Kidney Disease and Healthy Controls: Relationships to Ambulatory 24-Hour Blood Pressure and Echocardiographic Measures

“…Inflammation induced by RAA within the vascular wall that includes the infiltration of T lymphocytes has been described as an important component in the development of hypertension by Guzik et al and Wei et al [14][15][16]. This is in line with our observation that CXCL12 concentration (as lymphocyte-attractant) correlates with SBP assessed by ABPM.…”

Hypertension and the Brain: A Risk Factor for More Than Heart Disease

“…Despite existing evidence linking endothelial activation and cSVD, the fact that elevated circulating markers of endothelial activation in patients with cSVD may derive from any vascular bed permits direct association of cerebro-endothelial activation, inflammation-induced artery stiffening and resulting impairment of auto-regulation of CBF. Nevertheless, there is evidence showing elevation of adhesion molecules, leukocyte rolling along cerebral vessels and T-cells infiltration and accumulation in perivascular spaces during hypertension that suggest a causative link between endothelial activation and cerebrovascular dysfunction [78][79][80] .…”

The role of chemokines in hypertension and consequent target organ damage

“…For example, T cells isolated from the aorta and kidney, but not the spleen and blood, of Ang II-infused mice produced more CCL2 upon T cell receptor stimulation compared to normotensive controls (45). Moreover, infiltrating T cells and monocytes/macrophages produce pro-inflammatory cytokines, such as TNF-α and IL-1β, that further induce CCL2 expression in resident tissue cells (46).…”