Role of chemokine RANTES in the regulation of perivascular inflammation, T‐cell accumulation, and vascular dysfunction in hypertension

Abstract

Recent studies have emphasized the role of perivascular inflammation in cardiovascular disease. We studied mechanisms of perivascular leukocyte infiltration in angiotensin II (Ang II)-induced hypertension and their links to vascular dysfunction. Chronic Ang II infusion in mice increased immune cell content of T cells (255 ± 130 to 1664 ± 349 cells/mg; P < 0.01), M1 and M2 macrophages, and dendritic cells in perivascular adipose tissue. In particular, the content of T lymphocytes bearing CC chemokine receptor (CCR) 1, CCR3, and CCR5 receptors for RANTES chemokine was increased by Ang II (CCR1, 15.6 ± 1.5% vs. 31 ± 5%; P < 0.01). Hypertension was associated with an increase in perivascular adipose tissue expression of the chemokine RANTES (relative quantification, 1.2 ± 0.2 vs. 3.5 ± 1.1; P < 0.05), which induced T-cell chemotaxis and vascular accumulation of T cells expressing the chemokine receptors CCR1, CCR3, and CCR5. Mechanistically, RANTES−/− knockout protected against vascular leukocyte, and in particular T lymphocyte infiltration (26 ± 5% in wild type Ang II vs. 15 ± 4% in RANTES−/−), which was associated with protection from endothelial dysfunction induced by Ang II. This effect was linked with diminished infiltration of IFN-γ-producing CD8+ and double-negative CD3+CD4−CD8− T cells in perivascular space and reduced vascular oxidative stress while FoxP3+ T-regulatory cells were unaltered. IFN-γ ex vivo caused significant endothelial dysfunction, which was reduced by superoxide anion scavenging. In a human cohort, a significant inverse correlation was observed between circulating RANTES levels as a biomarker and vascular function measured as flow-mediated dilatation (R = −0.3, P < 0.01) or endothelial injury marker von Willebrand factor (R = +0.3; P < 0.01). Thus, chemokine RANTES is important in the regulation of vascular dysfunction through modulation of perivascular inflammation.—Mikolajczyk, T. P., Nosalski, R., Szczepaniak, P., Budzyn, K., Osmenda, G., Skiba, D., Sagan, A., Wu, J., Vinh, A., Marvar, P. J., Guzik, B., Podolec, J., Drummond, G., Lob, H. E., Harrison, D. G., Guzik, T. J. Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension.

A salt-sensing kinase in T lymphocytes, SGK1, drives hypertension and hypertensive end-organ damage

“…T cell SGK1 deficiency prevents Ang II-induced vascular and renal inflammation. We and others have shown that Ang II increases total leukocyte and T cell infiltration into the perivascular fat and kidneys, and that this is likely an important causal factor for the progression of hypertension and the development of end-organ damage (4,14,15). To determine the role of T cell SGK1 on vascular and renal inflammation, we performed flow cytometry on single-cell suspensions of the thoracic aorta and kidney following 7 and 28 days of Ang II infusion in SGK1 (B-D) Summary data of absolute numbers of indicated cell types per thoracic aorta.…”

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

“…17,[67][68][69][70] Oxidative stress is central in the pathology both as an initiator of vascular and renal inflammation and the consequence of inflammatory responses and cytokines. [71][72][73] This is particularly important, in light of the role of immunosenescent T cells in hypertension and the susceptibility of T cells to changes associated with aging. 74 They are characterized by loss of CD28 marker and appearance of CD57 and functionally produce tumor necrosis factor-α and interferon-γ, which affect vascular changes.…”

Plasma SCF/c-kit Levels in Patients with Dipper and Non-Dipper Hypertension

“…14 Stiffness, vascular resistance, remodeling, and endothelial dysfunction are hallmarks of hypertension. 15,16 The clinical relevance of a non-dipping status in hypertensive patients increases the risk for cardiovascular events. 17 The endothelium-dependent vasodilatation is much more impaired in non-dippers.…”