Oxidative Stress and the Vascular Wall

The contemporary notion that oxidative stress contributes to vascular wall pathology dates back some 25 years, when chemical modification of LDL was found to permit macrophage foam cell formation,1 and subsequent data indicated that vascular cells promoted LDL lipid oxidation (eg, LDL oxidation) to produce a similarly modified LDL.2 It is now clear, however, that oxidative stress in the vascular wall involves much more than the oxidation of LDL lipids. Risk factors for atherosclerosis are associated with an increased arterial wall flux of reactive oxygen species that not only may oxidize biological targets (ie, lipids), but also directly produce phenotypic changes in vascular cells such as inducing smooth muscle cell proliferation, adhesion molecule expression, and premature senescence.3 Many of these cellular responses have been implicated in both the development and the clinical manifestations of atherosclerosis.Articles pp 2668 and 2677 In the cellular environment, the most common reactive oxygen species produced is superoxide (O2·−) because it is the product of a single electron added to oxygen. Cells and tissues contain abundant superoxide dismutase that converts superoxide to hydrogen peroxide (H2O2), a species that has garnered considerable interest as an endogenous signaling molecule. A landmark study by Sundaresan and colleagues7 demonstrated a requirement for intracellular H2O2 generation in the mitogenic effects of platelet-derived growth factor on smooth muscle. Subsequent investigation points to a host of phenotypic responses that involve intracellular reactive oxygen species as signaling molecules (reviewed by Chen et al8). As a result of this body of work, one can construct a paradigm (Figure 1) relating cellular responses to the phenotype of the vascular wall. In this model, the presence or absence of vascular disease represents a balance between tissue responses typically categorized as either normal …