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

Tomasz P. Mikolajczyk, Ryszard Nosalski, Piotr Szczepaniak, Klaudia Budzyn, Grzegorz Osmenda, Dominik Skiba, Agnieszka Sagan, Jing Wu, Antony Vinh, Paul J. Marvar, Bartlomiej Guzik, Jakub Podolec, Grant Drummond, Heinrich E. Lob, David G. Harrison, Tomasz J. Guzik

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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+CD4CD8 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.
Original languageEnglish
Pages (from-to)1987-1999
Number of pages13
JournalFASEB Journal
Volume30
Issue number5
DOIs
Publication statusPublished - May 2016

Keywords

  • blood pressure
  • endothelial function
  • vascular inflammation
  • immune activation
  • superoxide

Cite this

Mikolajczyk, Tomasz P. ; Nosalski, Ryszard ; Szczepaniak, Piotr ; Budzyn, Klaudia ; Osmenda, Grzegorz ; Skiba, Dominik ; Sagan, Agnieszka ; Wu, Jing ; Vinh, Antony ; Marvar, Paul J. ; Guzik, Bartlomiej ; Podolec, Jakub ; Drummond, Grant ; Lob, Heinrich E. ; Harrison, David G. ; Guzik, Tomasz J. / Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension. In: FASEB Journal. 2016 ; Vol. 30, No. 5. pp. 1987-1999.
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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.",
keywords = "blood pressure, endothelial function, vascular inflammation, immune activation, superoxide",
author = "Mikolajczyk, {Tomasz P.} and Ryszard Nosalski and Piotr Szczepaniak and Klaudia Budzyn and Grzegorz Osmenda and Dominik Skiba and Agnieszka Sagan and Jing Wu and Antony Vinh and Marvar, {Paul J.} and Bartlomiej Guzik and Jakub Podolec and Grant Drummond and Lob, {Heinrich E.} and Harrison, {David G.} and Guzik, {Tomasz J.}",
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language = "English",
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Mikolajczyk, TP, Nosalski, R, Szczepaniak, P, Budzyn, K, Osmenda, G, Skiba, D, Sagan, A, Wu, J, Vinh, A, Marvar, PJ, Guzik, B, Podolec, J, Drummond, G, Lob, HE, Harrison, DG & Guzik, TJ 2016, 'Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension', FASEB Journal, vol. 30, no. 5, pp. 1987-1999. https://doi.org/10.1096/fj.201500088R

Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension. / Mikolajczyk, Tomasz P.; Nosalski, Ryszard; Szczepaniak, Piotr; Budzyn, Klaudia; Osmenda, Grzegorz; Skiba, Dominik; Sagan, Agnieszka; Wu, Jing; Vinh, Antony; Marvar, Paul J.; Guzik, Bartlomiej; Podolec, Jakub; Drummond, Grant; Lob, Heinrich E.; Harrison, David G.; Guzik, Tomasz J.

In: FASEB Journal, Vol. 30, No. 5, 05.2016, p. 1987-1999.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension

AU - Mikolajczyk, Tomasz P.

AU - Nosalski, Ryszard

AU - Szczepaniak, Piotr

AU - Budzyn, Klaudia

AU - Osmenda, Grzegorz

AU - Skiba, Dominik

AU - Sagan, Agnieszka

AU - Wu, Jing

AU - Vinh, Antony

AU - Marvar, Paul J.

AU - Guzik, Bartlomiej

AU - Podolec, Jakub

AU - Drummond, Grant

AU - Lob, Heinrich E.

AU - Harrison, David G.

AU - Guzik, Tomasz J.

PY - 2016/5

Y1 - 2016/5

N2 - 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.

AB - 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.

KW - blood pressure

KW - endothelial function

KW - vascular inflammation

KW - immune activation

KW - superoxide

UR - http://www.ncbi.nlm.nih.gov/pubmed/26873938

U2 - 10.1096/fj.201500088R

DO - 10.1096/fj.201500088R

M3 - Article

VL - 30

SP - 1987

EP - 1999

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 5

ER -