Reactive Oxygen Species in Endothelial Function　– From Disease to Adaptation –

Abstract

Endothelial function is largely dictated by its ability to rapidly sense environmental cues and adapt to these stimuli through changes in vascular tone, inflammation/immune recruitment, and angiogenesis. When any one of these abilities is compromised, the endothelium becomes dysfunctional, which ultimately leads to disease. Reactive oxygen species (ROS) have been established at the forefront of endothelial dysfunction; however, more careful examination has demonstrated that ROS are fundamental to each of the sensing/signaling roles of the endothelium. The purpose of this review is to document endothelial ROS production in both disease and physiological adaptation. Through understanding new endothelial signaling paradigms, we will gain insight into more targeted therapeutic strategies for vascular diseases. 1146CRAIGE SM et al.function is not new. It was noted more than 60 years ago that antioxidant supplementation of model organisms improved maximum lifespan. From this observation Denman Harman developed the "oxidative theory of aging", which suggests ROS-mediated damage to macromolecules (eg, DNA, RNA, protein) over one's lifetime leads to the manifestations of aging. 18 Many other conditions are known to involve oxidative stress, broadly defined as an excess of oxidants over the species required to detoxify them. 19 These earlier concepts concerning ROS biology typically focused on their potential for damaging cellular components. Because oxygen is a ubiquitous component of higher order biologic systems, it is not surprising that ROS can be generated by diverse cellular processes such as mitochondrial electron transfer, drug detoxification by cytochrome p450s, uncoupling of eNOS, and an array of oxidase enzymes such as xanthine oxidase and NADPH oxidases, among others. The most facile ROS produced in biological systems is O2 •− , as it requires only a single-electron reduction of molecular oxygen (Figure 1). The most common fates for O2 •− (based upon rate constants) are dismutation to H2O2 or its reaction with NO • to form ONOO − . In specific circumstances that involve accessible redox-active metal ions (which are rare in vivo), O2 •− can also undergo sequential reduction.In addition to their role in mediating cellular damage (typically at high concentrations), low level ROS production has been implicated in cellular signaling. 20 In this context it is important to consider the specific properties of distinct ROS that may dictate the types of signaling to which they are best suited. Superoxide has been implicated in signaling, but it is a charged species that cannot cross membranes, suggesting it is best suited for very local signal propagation. Moreover, O2 •− is subject to both spontaneous (rate constant=8×10 4 M −1 s −1 ), and enzymatic (rate constant=2×10 9 M −1 s −1 ) dismutation to H2O2. Given that most cells and cellular compartments have abundantly available SOD, one must consider that O2 •− is likely to have a very short half-life in biological systems. Conversely, H2O2 is a relatively stable 2-ele...

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