Abstract
Blood flow characteristics influence endothelial cell apoptosis. However, little is known about the occurrence of endothelial cell apoptosis in human atherosclerosis and its relation to blood flow. A total of 42 human carotid atherosclerotic plaques were retrieved by endarterectomy; they were examined in the longitudinal axial direction. Plaques were included in this study when upstream and downstream parts were clearly visible, occlusion was absent, and immunostaining for luminal endothelium was present all along the plaque. Using these criteria, 13 plaques were processed for further immunohistochemical studies (using anti-CD31, anti-Ki-67, and anti-splicing factor antibodies) and in situ detection of apoptosis (terminal dUTP nick end-labeling and ligase assay). Eight plaques showed > or =1 apoptotic endothelial cell at the luminal surface. Quantitative analysis of endothelial cell apoptosis in these plaques showed a systematic preferential occurrence of apoptosis in the downstream parts of plaques, where low flow and low shear stress prevail, in comparison with the upstream parts (18.8+/-3.3% versus 2.7+/-1.2%, respectively, P<0.001). Endothelial cell apoptosis was barely detectable in plaque microvessels. Our results suggest that in vivo local shear stress influences luminal endothelial cell apoptosis and may be a major determinant of plaque erosion and thrombosis.
Highlights
MethodsA total of 42 human atherosclerotic plaques that were removed from 42 patients undergoing en bloc carotid endarterectomy were collected
Blood flow characteristics influence endothelial cell apoptosis
These areas are characterized by increased endothelial cell turnover rates,[3] suggesting increased cell death. This view is supported by recent studies showing that endothelial cells cultured under static conditions undergo apoptosis, whereas normal levels of shear stress are protective.[4,5,6]. These data suggest a mechanistic link between low shear stress, endothelial cell apoptosis, and the susceptibility to plaque development.[7]
Summary
A total of 42 human atherosclerotic plaques that were removed from 42 patients undergoing en bloc carotid endarterectomy were collected. The plaques were immediately fixed in 4% paraformaldehyde and frozen in mounting medium (OCT Compound, Miles Inc, Diagnosis Division). Longitudinal cryostat sections (5 to 6 m) of the whole plaque were obtained in a direction parallel to the long axis of the artery. The upstream part of the plaque was defined as the area between the beginning of the plaque and the site of maximal stenosis. The downstream part was defined as the area between the site of maximal stenosis and the end of the plaque. Plaques were included in this study when upstream and downstream parts were clearly visible, occlusion was absent, and immunostaining for luminal endothelium was present all along the plaque.
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