Abstract 14417: M2 Macrophage Polarization is a Cause of Vascular Fibrosis and Stiffening in Hypertension
Arterial stiffening is a hallmark of hypertension and contributes to elevated systolic blood pressure (SBP), increased cardiac afterload, poor coronary perfusion and end organ damage. Hypertension is also associated with accumulation of macrophages in the vascular wall, which can exist as pro-inflammatory M1 or anti-inflammatory/pro-fibrotic M2 phenotypes. We hypothesized that accumulation of M2 macrophages in the vascular wall during hypertension is a major cause of arterial stiffening associated with the condition. Infusion of Ang II (0.7 mg/kg/d, s.c., 28 d) into male C57BL6/J mice caused a marked increase in SBP, reaching a plateau within 5 d and remaining elevated for the remainder of the treatment period (161±2 mmHg vs 119±2 mmHg in saline group; n≥16, P<0.05). In vitro analysis of the length-tension relationship of isolated aortic rings demonstrated that Ang II treatment was also associated with a marked (~15%) reduction in arterial compliance (n≥5; P<0.05). Flow cytometric analysis revealed that Ang II infusion caused a 2-fold increase in macrophage accumulation (CD45+F4/80+) in the aortic wall with the majority of these cells being M2 polarised, as indicated by their expression of CD206. This was further confirmed by real-time PCR and the demonstration of a 2-fold increase in mRNA expression of the M2 macrophage markers arginase-1 and Fc receptor-like S scavenger receptor (n=4; P<0.05) in aortic homogenates from Ang II- versus saline-infused mice, with no changes in expression of the M1 markers inducible nitric oxide synthase, CXCL2 and tumour necrosis factor. Treatment of Ang II-infused mice with clodronate-encapsulated liposomes (50 mg/kg/d, i.v.) resulted in a ~70% reduction in circulating monocytes (Ly6C+), and prevented the accumulation of M2 macrophages in the artery wall. Clodronate treatment also improved arterial compliance (n=4-5; P<0.05) and reduced SBP in Ang II-treated mice by 20-25 mmHg (n=9-10; P<0.05). In conclusion, monocyte depletion and consequent inhibition of M2 macrophage accumulation in the aortic wall improves arterial compliance and reduces SBP in Ang II-treated mice. These findings imply that strategies that prevent M2 macrophage polarization hold promise as future therapies for the treatment of hypertension.
- © 2013 by American Heart Association, Inc.