Prolonged Infusion of Angiotensin II in apoE−/− Mice Promotes Macrophage Recruitment with Continued Expansion of Abdominal Aortic Aneurysm

Abstract

Angiotensin II (AngII) infusion initiates abdominal aortic aneurysm (AAA) development due to medial disruption and results in luminal dilation and thrombus formation. The objective of this study was to determine whether AAA progressed during protracted AngII infusion. Male apoE(-/-) mice were infused with AngII using miniosmotic pumps. On day 27, suprarenal aortic luminal diameters were ultrasonically measured to identify mice exhibiting AAAs. Mice were designated to three groups with similar mean luminal dilation. Group 1 mice were sacrificed on day 28. Group 2 and 3 mice were subsequently infused with saline or AngII, respectively, for an additional 56 days. In Group 2, saline infusion-after the initial 28 days of AngII infusion-led to an immediate decrease in systolic blood pressure. Over the subsequent 56 days of saline infusion, there were no aneurysm-related deaths or significant changes in luminal diameter. In contrast, continuous AngII infusion in Group 3 maintained persistently increased systolic blood pressure, with aneurysmal rupture-associated deaths, increased luminal diameters, and tissue remodeling. Aortic aneurysmal segments that expanded during continuous AngII infusion exhibited macrophage accumulation in regions of medial disruption, predominantly on the adventitial aspect. Macrophages immunostained for CD206 more than for iNOS, consistent with an M2 phenotype. In conclusion, prolonged AngII infusion promotes AAA expansion, and is associated with enhanced rupture rates and increased macrophage infiltration.

CD16+Monocyte Subsets Are Increased in Large Abdominal Aortic Aneurysms and Are Differentially Related with Circulating and Cell-Associated Biochemical and Inflammatory Biomarkers

“…Male apoE(-/-) mice infused with Angiotensin II (AngII) to induce AAA showed presence of monocytederived macrophages in the media, adventitia and perivascular adipose tissue of new formed AAA; after long-term infusion (3 months) of AngII, macrophages became the predominant leukocyte population within AAA [9]. Similar pathologic features have been demonstrated in human AAAs, suggesting that local vascular inflammation contributes to AAAs [10].…”

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

“…AngII is required for AAA progression in ApoE −/− mice. 35 In contrast, several previous studies suggest that aortic remodeling continues after AngII infusion is completed with continued increases in proteolytic enzymes and inflammation. 36,37 Continued infusion of AngII is required for sustained increase in blood pressure, although previous studies suggest that AAA promoting properties of AngII are distinct to those stimulating hypertension.…”

Characterization of a Resident Population of Adventitial Macrophage Progenitor Cells in Postnatal Vasculature

“…This fits with the proliferative, clonogenic nature of Sca-1 + CD45 + AMPCs, which are located to be able to contribute to the presence of MPS populations found in the adventitia of healthy arteries, 16 as well as the rapid expansion of adventitial macrophages that occurs during the development of atherosclerosis and aneurysms, where these cells also help regulate growth of pathogenic vasa vasorum. 2,26,27 We are currently focusing on the proangiogenic properties of Sca-1 + CD45 + AMPCs, which we hypothesize may underlie one of their major pathophysiological functions during arterial wall remodeling. Although our results indicate that adventitial progenitors may contribute to only a small proportion of neointimal leukocytes, alternative model systems, such as molecular fate-mapping and arterial graft interposition, will be required before definitively excluding a greater role for AMPCs as a source of locally maintained macrophages in atheroma.…”