Abstract
BackgroundEctopic angiogenesis within the intima and media is considered to be a hallmark of advanced vulnerable atherosclerotic lesions. Some studies have shown that specific matrix metalloproteinases (MMPs) might play different roles in angiogenesis. Therefore, we investigated the predominant effects of specific MMPs in intraplaque angiogenesis and plaque instability in a rabbit model of atherosclerosis.Methods and ResultsNew Zealand rabbits underwent balloon injury of the abdominal artery and ingestion of a high-cholesterol (1%) diet to establish an atherosclerotic animal model. At weeks 4, 6, 8, 10, and 12 after balloon injury, five rabbits were euthanized and the abdominal aorta was harvested. Blood lipid analysis, intravascular ultrasound imaging, pathologic and immunohistochemical expression studies, and western blotting were performed. From weeks 4 to 12, the expression of MMP-1, -2, -3, and -9 and vascular endothelial growth factor A (VEGF-A) increased with atherosclerotic plaque development in the abdominal aorta, while the expression of MMP-14 substantially decreased. The vulnerability index (VI) gradually increased over time. Intraplaque neovessels appeared at week 8. The microvessel density (MVD) was greater at week 12 than at week 8. The VI, MVD, and VEGF-A level were positively correlated with the MMP-1, -2,-3, and -9 levels within plaques. Negative correlations were noted between the MMP-14 level and the VI, MVD, and VEGF-A level.ConclusionUpregulation of MMP-1, -2, -3, and -9 and downregulation of MMP-14 may contribute to intraplaque angiogenesis and plaque instability at the advanced stage of atherosclerosis in rabbits.
Highlights
Atherosclerotic plaque rupture is a major cause of acute cardiovascular events
The vulnerability index (VI), microvessel density (MVD), and vascular endothelial growth factor A (VEGF-A) level were positively correlated with the matrix metalloproteinases (MMPs)-1, -2,3, and -9 levels within plaques
Negative correlations were noted between the MMP-14 level and the VI, MVD, and VEGF-A level
Summary
Atherosclerotic plaque rupture is a major cause of acute cardiovascular events. stabilization of vulnerable plaques is of great clinical importance [1]. Pathological studies have identified specific characteristics of atherosclerotic plaques that are associated with plaque instability and rupture, including the ongoing inflammatory response, matrix degradation, and cell death. These changes result in eventual thinning of the fibrous cap and an increase in the inflammatory and necrotic core content. Neovessels within plaques are characterized by fragility and high perfusion, allowing for extravasation of lipoproteins and red blood cells that contribute to the formation of plaque lipids [3] This process results in intraplaque hemorrhage, increases the permeability of inflammatory cells, and leads to plaque destabilization [4,5]. We investigated the predominant effects of specific MMPs in intraplaque angiogenesis and plaque instability in a rabbit model of atherosclerosis
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