The endothelium plays a pivotal role in vascular homeostasis. Its strategic location between the vascular wall and the circulation allows it to serve as a bridge between these two compartments. A dynamic interaction exists between the endothelium and hormonal and cellular mediators, both from the circulation as well as from the vascular wall. This same strategic location of the endothelium also makes it a prime target for injury in the setting of vascular disease.

Accumulating evidence suggests that oxidative stress, by resulting in a maladaptive endothelial cell (EC) phenotype, is one of the common means by which conditions such as hyperlipidemia, hypertension, advanced age, hyperhomocysteinemia, and diabetes, all of which are associated with an increased risk of vascular diseases, lead to a dysfunctional endothelium. However, the term oxidative stress is loosely used and applied, and it would be simplistic to conclude that oxidants or reactive oxygen species (ROS) always play a pathophysiological role in the endothelium.

HISTORICAL PERSPECTIVE

ROS have been regarded historically as deleterious due to free radical–induced oxidation and damage of macromolecules such as DNA, proteins, and lipids. More recently, however, it has been appreciated that ROS can exert more subtle modulatory effects. This evolution in our understanding of the roles of ROS is exemplified by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a source of ROS in many cell types. The NADPH oxidase was first described in professional phagocytic cells (macrophages and neutrophils) of the innate immune system, where it is responsible for generating a large amount of the ROS superoxide as part of the oxidative burst during the process of phagocytosis (1).