Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are highly reactive byproducts of O2 metabolism that play an important physiological role in vascular biology and a pathophysiological role in hypertensive vascular disease.1,2 Under normal conditions, the rate of ROS production is balanced by the rate of elimination. However, a mismatch between ROS formation and the ability to defend against them by antioxidants results in increased bioavailability of ROS leading to a state of oxidative stress.2,3 The pathogenic outcome of oxidative stress is oxidative damage, a major cause of vascular injury in hypertension. Among the major ROS important in these processes are superoxide anion (*O2-), hydrogen peroxide (H2O2), hydroxyl radical (*OH), hypochlorous acid (HOCl) and the RNS, nitric oxide (NO), and peroxynitrite (ONOO-). Under physiological conditions, ROS/RNS are produced in a controlled manner at low concentrations and function

J.L. Holtzman (ed.), Atherosclerosis and Oxidant Stress: A New Perspective. © Springer 2007

as signaling molecules to maintain vascular integrity by regulating vascular smooth muscle cell contraction-relaxation and vascular smooth muscle cell growth.4-7 Under pathological conditions, increased production of ROS leads to endothelial dysfunction, increased contractility, vascular smooth muscle cell growth and apop-tosis, monocyte migration, lipid peroxidation, inflammation, and increased deposition of extracellular matrix proteins, major processes contributing to vascular damage in hypertension.7-9

In experimental models of hypertension, production of cardiac, renal, neural, and vascular ROS is increased.10-13 In human hypertension, plasma and urine levels of thiobarbituric acid-reactive substances (TBARS) and 8-epi-isoprostane, markers of systemic oxidative stress, are elevated.1415 Treatment with antioxidants or superoxide dismutase (SOD) mimetics improves vascular function and structure and reduces blood pressure in experimental and human hypertension.12131617 Mouse models deficient in ROS-generating oxidases have lower blood pressure compared with wild-type counterparts and Ang II infusion in these mice does not increase blood pressure.1819 Furthermore, in cultured vascular smooth muscle cells (VSMC) and isolated arteries from hypertensive rats and humans, production of ROS is enhanced and antioxidant capacity is reduced.1213,20 Accordingly, evidence at multiple levels supports a role for oxidative stress in the pathogenesis of hypertension.

The cardiovascular, renal, and central nervous systems, all important in the development of hypertension, are major targets for oxidative damage by ROS. The present review focuses on the role of oxidative stress in the vasculature in hypertension. The reader is referred to excellent reviews on the other systems.21-23 Here, we will discuss recent progress in mechanisms whereby ROS are generated in vascular cells, particularly with respect to NAD(P)H oxidase and NOS uncoupling, how ROS influence vascular function, and what the implications of oxi-dative stress are in hypertensive vascular injury. Finally strategies to counter oxidative stress-induced vascular damage as a putative therapeutic modality in the management of hypertension are discussed.

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