Expansive arterial remodeling is associated with increased neointimal macrophage foam cell content: the murine model of macrophage-rich carotid artery lesions.
BACKGROUND
Recent observations associate plaque instability with expansive arterial remodeling, suggesting a common driving mechanism.


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 (r2=0.600, P<0.001). 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.
Ivan
Eugen
E
Division of Cardiology, Emory University School of Medicine, Atlanta, Ga 30322, USA.
Khatri
Jaikirshan J
JJ
Johnson
Chad
C
Magid
Richard
R
Godin
Denis
D
Nandi
Sudeshna
S
Lessner
Susan
S
Galis
Zorina S
ZS
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002340:Carotid Artery Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002452:Cell Count; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000201:enzymology / Q000473:pathology; D005487:Foam Cells / Q000473:pathology*; D007150:Immunohistochemistry; D008026:Ligation; D008264:Macrophages / Q000473:pathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017539:Tunica Intima / Q000201:enzymology / Q000473:pathology*
D001057:Apolipoproteins E; D020780:Matrix Metalloproteinase 9