Abstract 448: A CCR2 Anatagonist Reduces Vascular Fibrosis, Macrophage Accumulation and Blood Pressure in Angiotensin II-Treated Mice
Macrophages accumulate in the vascular wall during hypertension. However, their contribution to vascular remodeling remains to be established. In the present study we examined the polarization state of macrophages (M1/M2) in the aorta during experimental hypertension. We also investigated whether pharmacological antagonism of the chemokine receptors involved in macrophage accumulation reduces vascular remodeling and/or blood pressure (BP). Mice treated with angiotensin II (Ang II; 0.7 mg/kg/d) displayed elevated systolic BP (158±3 mmHg) compared with saline-treated animals (122±3 mmHg; P<0.001). Flow cytometry revealed that Ang II infusion caused a 2-fold increase in aortic macrophage (F4/80+) numbers (P<0.01), and that the majority of these cells expressed the M2 marker, CD206. A PCR array to identify chemokine receptor targets for pharmacological intervention revealed CCR2 and its ligand CCL8 to be upregulated by 2-fold and 4-fold, respectively in aortas from Ang II-treated mice (P<0.05). Taqman real-time PCR confirmed these findings and showed a significant positive correlation between CCR2 and CD206 expression in the vessel wall (P<0.001), suggesting that M2 macrophages were a source of this chemokine receptor. Intervention with a CCR2 antagonist (INCB3344, 30 mg/kg/d), commencing 7 d after initiation of Ang II infusion and continuing for a further 21 d, reduced macrophage accumulation in the aorta by ~60% (P<0.001). INCB334 completely prevented Ang II-induced increases in aortic collagen deposition and elastin breakdown (P<0.05), and tended to reduce vessel stiffening. Moreover, at the end of the treatment period, Ang II-infused mice that received INCB3344 had markedly lower systolic BP and heart weight to body weight ratios (137±4 mmHg and 5.5±0.1 mg/g, respectively) than did Ang II-infused animals that received vehicle (158±3 mmHg and 6.4±0.4 mg/g; P<0.05 for both parameters). Thus, CCR2 is crucial for M2 macrophage accumulation in the aorta during Ang II infusion in mice and may represent a promising target for future therapies aimed at reducing vascular fibrosis, cardiac hypertrophy and BP in hypertension.
Author Disclosures: G.R. Drummond: None. J.P. Moore: None. S. Sakkal: None. S.M. Krishnan: None. C.S. Samuel: None. H. Diep: None. B.K. Kemp-Harper: None. A. Vinh: None. S.L. Ricardo: None. T.J. Guzik: None. C.G. Sobey: None.
- © 2014 by American Heart Association, Inc.