Disturbed blood flow induces erosive injury to smooth muscle cell-rich neointima and promotes thrombus formation in rabbit femoral arteries.

BACKGROUND: Plaque erosion is a cause of atherothrombosis that preferentially occurs on smooth muscle cell (SMC)- and proteoglycan-rich rather than lipid-rich plaques. However, its underlying mechanisms remain unknown. OBJECTIVE: To determine whether disturbed blood flow induces erosive injury and thrombus formation on SMC-rich neointima. METHODS: Three weeks after balloon injury, SMC-rich neointima with increased tissue factor (TF) activity developed in rabbit femoral arteries that were narrowed with a vascular occluder to disturb blood flow after stenosis. Neointimal injury and thrombus formation were assessed at 15, 30, and 180 min after the vascular narrowing. RESULTS: Endothelial detachment, platelet adhesion and neointimal cell apoptosis became evident at the post-stenotic regions of all femoral arteries (n = 5) within 15 min of narrowing. Mural thrombi composed of platelet and fibrin developed after 30 min, and then occlusive thrombi were generated in three out of five vessels after 180 min. The identical vascular narrowing of normal femoral arteries also induced endothelial detachment with small platelet thrombi at post-stenotic regions, but fibrin and occlusive thrombi did not develop. Computational simulation analysis indicated that oscillatory shear stress contributes to the development of erosive damage to the neointima. CONCLUSIONS: These results suggest that disturbed post-stenotic blood flow can induce erosive injury in SMC-rich plaques and promote thrombus formation that results in vascular events.

Medial and adventitial macrophages are associated with expansive atherosclerotic remodeling in rabbit femoral artery.

Expansive vascular remodeling is considered a feature of vulnerable plaques. Although inflammation is upregulated in the media and adventitia of atherosclerotic lesions, its contribution to expansive remodeling is unclear. We investigated this issue in injured femoral arteries of normo- and hyperlipidemic rabbits fed with a conventional (CD group; n=20) or a 0.5% cholesterol (ChD group; n=20) diet. Four weeks after balloon injury of the femoral arteries, we examined vascular wall alterations, localization of macrophages and matrix metalloproteases (MMP)-1, -2, -9, and extracellular matrix. Neointimal formation with luminal stenosis was evident in both groups, while expansive remodeling was observed only in the ChD group. Areas immunopositive for macrophages, MMP-1, -2 and -9 were larger not only in the neointima, but also in the media and/or adventitia in the injured arterial walls of the ChD, than in the CD group. Areas containing smooth muscle cells (SMCs), elastin and collagen were smaller in the injured arterial walls of the ChD group. MMP-1, -2 and -9 were mainly localized in infiltrating macrophages. MMP-2 was also found in SMCs and adventitial fibroblasts. Vasa vasorum density was significantly increased in injured arteries of ChD group than in those of CD group. These results suggest that macrophages in the media and adventitia play an important role in expansive atherosclerotic remodeling via extracellular matrix degradation and SMC reduction.