13.12 - Oxidants and Endothelial Dysfunction

Abstract

The vascular endothelium is a dynamic structure with many important functions in the vasculature, including maintenance of vascular tone through balancing factors that mediate vasoconstriction and vasodilation, regulation of vascular smooth muscle cell proliferation and migration, transport of biologically active molecules, inflammation, adhesiveness of platelets, and fibrinolysis. When the balance of these processes mediated by the endothelium is disrupted, endothelial dysfunction results. Clinically, endothelial dysfunction results in impaired endothelium-dependent vasorelaxation, primarily due to decreased NO bioavailability, the degree of which is an independent factor used for prognosis of patients with cardiovascular disease. Endothelial dysfunction is believed to play a pivotal role in the development, progression, and clinical complications of several cardiovascular diseases, including atherosclerosis, hypertension, coronary artery disease, and heart failure, as well as disease states such as diabetes and obesity, which are known risk factors for cardiovascular disease. In recent years, reactive oxygen species (ROS) have emerged as the major contributing factor in the pathogenesis of endothelial dysfunction. NAD(P)H oxidase is the primary producer of vascular ROS; however, xanthine oxidase, mitochondrial respiration, and ‘uncoupled’ endothelial nitric oxide synthase (eNOS) also contribute to endothelial ROS levels. Importantly, ROS have a significant role in promoting endothelial dysfunction directly through NO sequestration, thereby rendering it unavailable to function in vasodilation, as well as indirectly through mediating activation of key signal transduction pathways and transcriptional factors, as well as protein modification. While some therapeutic options for endothelial dysfunction exist (i.e., antioxidants, statins, and inhibitors of the renin–angiotensin system), to date none have been unequivocally shown to resolve endothelial dysfunction and improve vascular function. Further insight into the mechanisms of endothelial cell dysfunction, and its role in the progression of cardiovascular disease, is essential to identify effective therapeutic targets.