M2 macrophage accumulation in the aortic wall during angiotensin II infusion in mice is associated with fibrosis, elastin loss, and elevated blood pressure

Jeffrey P Moore, Antony Vinh, Kellie L Tuck, Samy Sakkal, Shalini Krishnan, Christopher Chan, Maggie Lieu, Chrishan S Samuel, Henry Diep, Barbara Kathryn Harper, Marianne Tare, Sharon D Ricardo, Tomasz J Guzik, Christopher G Sobey, Grant R Drummond

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Macrophages accumulate in blood vessels during hypertension. However, their contribution to vessel remodeling is unknown. Here we examined the polarization state of macrophages (M1/M2) in aortas of mice during hypertension and investigated whether antagonism of chemokine receptors involved in macrophage accumulation reduces vessel remodeling and blood pressure (BP). Mice treated with angiotensin II (0.7 mg.kg-1.d-1, 14 d) had elevated systolic BP (158+/-3 mmHg) compared to saline-treated animals (122+/-3 mmHg). Flow cytometry revealed that angiotensin II infusion increased numbers of CD45+CD11b+Ly6Chi monocytes and CD45+CD11b+F4/80+ macrophages by 10-fold and 2-fold, respectively. The majority of macrophages were positive for the M2 marker, CD206, but negative for the M1 marker, iNOS. Expression of other M2 genes (arginase-1, Fc scavenger receptor-like, receptor-1) was elevated in aortas from angiotensin II-treated mice, whereas M1 genes (tumour necrosis factor, CXCL2) were unaltered. A PCR array to identify chemokine receptor targets for intervention revealed CCR2 to be upregulated in aortas from angiotensin II-treated mice, while flow cytometry identified Ly6Chi monocytes as the main CCR2-expressing cell type. Intervention with a CCR2 antagonist (INCB3344, 30 mg.kg-1.d-1), 7 days after commencing angiotensin II infusion, reduced aortic macrophage numbers. INCB334 also reduced aortic collagen deposition, elastin loss and BP in angiotensin II-treated mice. Thus, angiotensin II-dependent hypertension in mice is associated with Ly6Chi monocyte and M2 macrophage accumulation in the aorta. Inhibition of macrophage accumulation with a CCR2 antagonist prevents angiotensin II-induced vessel fibrosis and elevated BP, highlighting this as a promising approach for the future treatment of vessel remodeling/stiffening in hypertension.
Original languageEnglish
Pages (from-to)906 - 917
Number of pages12
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume309
Issue number5
DOIs
Publication statusPublished - 2015

Cite this

@article{27fb0df8c08c431fa9f576b47ee1936f,
title = "M2 macrophage accumulation in the aortic wall during angiotensin II infusion in mice is associated with fibrosis, elastin loss, and elevated blood pressure",
abstract = "Macrophages accumulate in blood vessels during hypertension. However, their contribution to vessel remodeling is unknown. Here we examined the polarization state of macrophages (M1/M2) in aortas of mice during hypertension and investigated whether antagonism of chemokine receptors involved in macrophage accumulation reduces vessel remodeling and blood pressure (BP). Mice treated with angiotensin II (0.7 mg.kg-1.d-1, 14 d) had elevated systolic BP (158+/-3 mmHg) compared to saline-treated animals (122+/-3 mmHg). Flow cytometry revealed that angiotensin II infusion increased numbers of CD45+CD11b+Ly6Chi monocytes and CD45+CD11b+F4/80+ macrophages by 10-fold and 2-fold, respectively. The majority of macrophages were positive for the M2 marker, CD206, but negative for the M1 marker, iNOS. Expression of other M2 genes (arginase-1, Fc scavenger receptor-like, receptor-1) was elevated in aortas from angiotensin II-treated mice, whereas M1 genes (tumour necrosis factor, CXCL2) were unaltered. A PCR array to identify chemokine receptor targets for intervention revealed CCR2 to be upregulated in aortas from angiotensin II-treated mice, while flow cytometry identified Ly6Chi monocytes as the main CCR2-expressing cell type. Intervention with a CCR2 antagonist (INCB3344, 30 mg.kg-1.d-1), 7 days after commencing angiotensin II infusion, reduced aortic macrophage numbers. INCB334 also reduced aortic collagen deposition, elastin loss and BP in angiotensin II-treated mice. Thus, angiotensin II-dependent hypertension in mice is associated with Ly6Chi monocyte and M2 macrophage accumulation in the aorta. Inhibition of macrophage accumulation with a CCR2 antagonist prevents angiotensin II-induced vessel fibrosis and elevated BP, highlighting this as a promising approach for the future treatment of vessel remodeling/stiffening in hypertension.",
author = "Moore, {Jeffrey P} and Antony Vinh and Tuck, {Kellie L} and Samy Sakkal and Shalini Krishnan and Christopher Chan and Maggie Lieu and Samuel, {Chrishan S} and Henry Diep and Harper, {Barbara Kathryn} and Marianne Tare and Ricardo, {Sharon D} and Guzik, {Tomasz J} and Sobey, {Christopher G} and Drummond, {Grant R}",
year = "2015",
doi = "10.1152/ajpheart.00821.2014",
language = "English",
volume = "309",
pages = "906 -- 917",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "5",

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TY - JOUR

T1 - M2 macrophage accumulation in the aortic wall during angiotensin II infusion in mice is associated with fibrosis, elastin loss, and elevated blood pressure

AU - Moore, Jeffrey P

AU - Vinh, Antony

AU - Tuck, Kellie L

AU - Sakkal, Samy

AU - Krishnan, Shalini

AU - Chan, Christopher

AU - Lieu, Maggie

AU - Samuel, Chrishan S

AU - Diep, Henry

AU - Harper, Barbara Kathryn

AU - Tare, Marianne

AU - Ricardo, Sharon D

AU - Guzik, Tomasz J

AU - Sobey, Christopher G

AU - Drummond, Grant R

PY - 2015

Y1 - 2015

N2 - Macrophages accumulate in blood vessels during hypertension. However, their contribution to vessel remodeling is unknown. Here we examined the polarization state of macrophages (M1/M2) in aortas of mice during hypertension and investigated whether antagonism of chemokine receptors involved in macrophage accumulation reduces vessel remodeling and blood pressure (BP). Mice treated with angiotensin II (0.7 mg.kg-1.d-1, 14 d) had elevated systolic BP (158+/-3 mmHg) compared to saline-treated animals (122+/-3 mmHg). Flow cytometry revealed that angiotensin II infusion increased numbers of CD45+CD11b+Ly6Chi monocytes and CD45+CD11b+F4/80+ macrophages by 10-fold and 2-fold, respectively. The majority of macrophages were positive for the M2 marker, CD206, but negative for the M1 marker, iNOS. Expression of other M2 genes (arginase-1, Fc scavenger receptor-like, receptor-1) was elevated in aortas from angiotensin II-treated mice, whereas M1 genes (tumour necrosis factor, CXCL2) were unaltered. A PCR array to identify chemokine receptor targets for intervention revealed CCR2 to be upregulated in aortas from angiotensin II-treated mice, while flow cytometry identified Ly6Chi monocytes as the main CCR2-expressing cell type. Intervention with a CCR2 antagonist (INCB3344, 30 mg.kg-1.d-1), 7 days after commencing angiotensin II infusion, reduced aortic macrophage numbers. INCB334 also reduced aortic collagen deposition, elastin loss and BP in angiotensin II-treated mice. Thus, angiotensin II-dependent hypertension in mice is associated with Ly6Chi monocyte and M2 macrophage accumulation in the aorta. Inhibition of macrophage accumulation with a CCR2 antagonist prevents angiotensin II-induced vessel fibrosis and elevated BP, highlighting this as a promising approach for the future treatment of vessel remodeling/stiffening in hypertension.

AB - Macrophages accumulate in blood vessels during hypertension. However, their contribution to vessel remodeling is unknown. Here we examined the polarization state of macrophages (M1/M2) in aortas of mice during hypertension and investigated whether antagonism of chemokine receptors involved in macrophage accumulation reduces vessel remodeling and blood pressure (BP). Mice treated with angiotensin II (0.7 mg.kg-1.d-1, 14 d) had elevated systolic BP (158+/-3 mmHg) compared to saline-treated animals (122+/-3 mmHg). Flow cytometry revealed that angiotensin II infusion increased numbers of CD45+CD11b+Ly6Chi monocytes and CD45+CD11b+F4/80+ macrophages by 10-fold and 2-fold, respectively. The majority of macrophages were positive for the M2 marker, CD206, but negative for the M1 marker, iNOS. Expression of other M2 genes (arginase-1, Fc scavenger receptor-like, receptor-1) was elevated in aortas from angiotensin II-treated mice, whereas M1 genes (tumour necrosis factor, CXCL2) were unaltered. A PCR array to identify chemokine receptor targets for intervention revealed CCR2 to be upregulated in aortas from angiotensin II-treated mice, while flow cytometry identified Ly6Chi monocytes as the main CCR2-expressing cell type. Intervention with a CCR2 antagonist (INCB3344, 30 mg.kg-1.d-1), 7 days after commencing angiotensin II infusion, reduced aortic macrophage numbers. INCB334 also reduced aortic collagen deposition, elastin loss and BP in angiotensin II-treated mice. Thus, angiotensin II-dependent hypertension in mice is associated with Ly6Chi monocyte and M2 macrophage accumulation in the aorta. Inhibition of macrophage accumulation with a CCR2 antagonist prevents angiotensin II-induced vessel fibrosis and elevated BP, highlighting this as a promising approach for the future treatment of vessel remodeling/stiffening in hypertension.

UR - http://ajpheart.physiology.org/content/309/5/H906.full-text.pdf+html

U2 - 10.1152/ajpheart.00821.2014

DO - 10.1152/ajpheart.00821.2014

M3 - Article

VL - 309

SP - 906

EP - 917

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 5

ER -