Endothelial dysfunction is an established clinical marker of early coronary artery disease and has been shown to be associated with increased cardiovascular morbidity and mortality. New concepts now extend the view of endothelial dysfunction beyond the traditional involvement of the coronary arterial endothelium alone. Recent research indicates that the coronary vessel wall, especially the vasa vasorum, as well as bone marrow-derived endothelial progenitor cells may be subject to proatherosclerotic changes, even before the development of angiographically evident endothelial dysfunction; therefore, "microvascular endothelial dysfunction," which is composed of dysfunction of the vasa vasorum's endothelium as well as "microcellular endothelial dysfunction," reflecting impaired mobilization and function of endothelial progenitor cells, may precede "macrovascular endothelial dysfunction." Vasa vasorum neovascularization, with endothelial leakage and dysfunction increasing influx of proinflammatory and proatherogenic cellular and noncellular substances into the vessel wall, is proposed as one feature of this new concept. In addition, the role of bone marrow-derived endothelial progenitor cells is discussed as are the potential impact of impaired progenitor cell mobilization, release from the marrow, and function in acute and stable coronary artery disease. Finally, potential future therapies are proposed, focusing on interventions that may prevent or diminish the development of the microvascular and microcellular endothelial dysfunction.
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