Projects per year
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 language | English |
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Pages (from-to) | 906 - 917 |
Number of pages | 12 |
Journal | American Journal of Physiology - Heart and Circulatory Physiology |
Volume | 309 |
Issue number | 5 |
DOIs | |
Publication status | Published - 2015 |
Projects
- 4 Finished
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NHMRC Research Fellowship
National Health and Medical Research Council (NHMRC) (Australia)
1/01/13 → 31/12/18
Project: Research
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M2 macrophage polarization as a cause of vascular fibrosis and stiffening in hypertension
Drummond, G. & Sobey, C.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/13 → 31/12/15
Project: Research