Low thrombogenicity of calcified atherosclerotic plaques is associated with bone morphogenetic protein-2-dependent inhibition of tissue factor expression

Morphology of atherosclerotic plaque is a major determinant of plaque thrombogenicity. Calcified atherosclerotic lesions are less prone to thrombosis and contain less tissue factor (TF) than lipid-rich plaques. Although bone morphogenetic protein (BMP)-2 is a known mediator of vascular calcification, the role of BMP-2 in the regulation of plaque thrombogenicity has not been established. We hypothesized that the expression of BMP-2 within highly calcified atherosclerotic plaques inhibits TF expression and reduces thrombogenicity of calcified lesions. In the present study, we measured levels of TF and BMP-2 in human calcified and lipid-rich carotid plaques and studied the effects of BMP-2 on TF expression in human monocytes in vitro. Quantitative immunohistochemical analysis of endarterectomy specimens for TF and BMP-2 revealed that calcified plaques contained nearly three-times less TF antigen than lipid-rich ones. In contrast, calcified plaques expressed two-times more BMP-2 antigen than lipid-rich lesions. BMP-2 markedly decreased protein expression and surface redistribution of TF in activated human monocytes in vitro. BMP-2-mediated inhibition of TF expression in monocytes/macrophages could contribute to reduced thrombogenicity of calcified atherosclerotic plaques.