title: 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.
authors.affiliation: Department of Internal Medicine, Jagiellonian University, Cracow, Poland British Heart Foundation Centre for Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Tomasz P
authors.initials: TP
authors.lastname: Mikolajczyk
authors.affiliation: Department of Internal Medicine, Jagiellonian University, Cracow, Poland British Heart Foundation Centre for Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Ryszard
authors.initials: R
authors.lastname: Nosalski
authors.affiliation: Department of Internal Medicine, Jagiellonian University, Cracow, Poland British Heart Foundation Centre for Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Piotr
authors.initials: P
authors.lastname: Szczepaniak
authors.affiliation: Department of Pharmacology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Budzyn
authors.affiliation: Department of Internal Medicine, Jagiellonian University, Cracow, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Osmenda
authors.affiliation: Department of Internal Medicine, Jagiellonian University, Cracow, Poland British Heart Foundation Centre for Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Dominik
authors.initials: D
authors.lastname: Skiba
authors.affiliation: Department of Internal Medicine, Jagiellonian University, Cracow, Poland British Heart Foundation Centre for Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Sagan
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Antony
authors.initials: A
authors.lastname: Vinh
authors.affiliation: Department of Pharmacology and Physiology, George Washington University, Washington, D.C., USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Marvar
authors.affiliation: Department of Internal Medicine, Jagiellonian University, Cracow, Poland.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Guzik
authors.affiliation: Department of Internal Medicine, Jagiellonian University, Cracow, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Podolec
authors.affiliation: Department of Pharmacology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Grant
authors.initials: G
authors.lastname: Drummond
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, New York, USA.
authors.forename: Heinrich E
authors.initials: HE
authors.lastname: Lob
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
authors.affiliation: Department of Internal Medicine, Jagiellonian University, Cracow, Poland British Heart Foundation Centre for Excellence, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom tomasz.guzik@glasgow.ac.uk.
authors.forename: Tomasz J
authors.initials: TJ
authors.lastname: Guzik
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*; D014657:Vasculitis / Q000378:metabolism*
chemical_list: D018946:Chemokine CCL5; D000804:Angiotensin II; D007371:Interferon-gamma
keywords: blood pressure; endothelial function; immune activation; superoxide; vascular inflammation