Expansive Arterial Remodeling Is Associated With Increased Neointimal Macrophage Foam Cell Content

Abstract

Background-Recent observations associate plaque instability with expansive arterial remodeling, suggesting a common driving mechanism. Methods and Results-To demonstrate that macrophages, a characteristic of vulnerable plaques, also assist in expansive remodeling, we compared carotid artery remodeling due to formation of experimental macrophage-rich and macrophage-poor lesions in the flow cessation model in hypercholesterolemic apolipoprotein E knockout (ApoE KO) and wild type (WT) mice. After ligation, macrophages started to rapidly accumulate in ApoE KO but not in WT carotid artery lesions. Macrophage-rich ApoE KO intimal lesions grew fast, typically occluding within 14 days, despite a tripling of the vessel area. Outward remodeling of macrophage-rich ApoE KO arteries positively correlated with macrophage area (r 2 ϭ0.600, PϽ0.001). To investigate potential mechanisms of macrophage-enabled expansive remodeling, we compared levels of matrix metalloproteinases in homogenates of macrophage-rich and macrophage-poor carotid arteries. Gelatinolytic activity of macrophage-rich lesions increased faster and reached maximal levels several fold higher than in the macrophage-poor WT lesions. Conclusions-Our results suggest that macrophages facilitate expansive arterial remodeling through increased matrix degradation by matrix metalloproteinases. This initially favorable remodeling action may eventually increase the vulnerability of macrophage-rich atherosclerotic plaques.

Genetic determinants of vascular remodelling

“…In our recent study (1), there was a strong correlation between outward remodelling and IMT formation in the carotid. A similar correlation was previously reported for vessel and intima areas in the carotid flow cessation model in hypercholesterolemic ApoE knockout mice (68). Also of importance, we found that genetic background is a critical determinant of remodelling with unique responses among inbred strains.…”

Atherosclerotic Lesions Grow Through Recruitment and Proliferation of Circulating Monocytes in a Murine Model

“…Morphometric data obtained in the present study indicate that the time course of carotid lesion development and arterial remodeling closely follows that observed in our previous study in nontransplanted apoE KO mice. 21 In the mouse BMT model used in this study, replacement of host-type WBCs by donor-derived cells occurs much more slowly among macrophages in the carotid adventitia than among circulating monocytes. By 8 weeks after transplant, more than 80% of circulating WBCs originated from the donor bone marrow, whereas only ϳ55% of adventitial WBCs were donor-derived.…”

Atherosclerotic Lesion Size and Vulnerability Are Determined by Patterns of Fluid Shear Stress

“…Conversely, in the lesions induced by vortices with oscillatory shear stress, a thick, fibrous cap heavily infiltrated with vascular smooth muscle cells covered the lesion, which contained similar relative amounts of macrophages but fewer lipids than did the lesions in the lowered shear stress regions. Furthermore, outward vascular remodeling, which is considered one of the characteristic features of vulnerable plaques, 22 was more prominent in the lowered shear stress region. These findings indicate that oscillatory shear stress induces the growth of more stabilized plaques, whereas lowered shear stress initiates the development of lesions with a vulnerable phenotype.…”