Chapter 6

INTRODUCTION

It has become increasingly apparent that the atherosclerotic disease process begins early in life. Dynamic changes in vascular biology are involved in the initiation and progression of disease as well as in the destabilization of established plaques that gives rise to acute clinical events.1 The vascular endothelium has been shown to be the central regulator of vascular health, accomplished through the production of a wide range of factors that affect vascular tone, cellular adhesion, thrombosis, smooth muscle cell proliferation, and vessel wall inflammation as described in Chapter 5. Because of its intimate interface between the circulating blood and the vessel wall, it is ideally placed to function as an active signal transducer for circulating modulators of vessel wall biology.2 Alterations in endothelial function are the earliest pathological vascular changes that can be detected clinically. These typically precede the evolution of structural atherosclerotic disease, contributing mechanistically to lesion development and to later clinical complications.1

Appreciation of the central role of the endothelium throughout the atherosclerotic disease process has led to the development of a wide variety of tests to evaluate its various functional properties. These techniques have provided valuable insights into the role of the endothelium in the maintenance of a healthy circulation and the pathogenesis of arterial disease. These different methods will be discussed in this chapter in relation to the opportunities provided for the detection of preclinical disease, understanding the impact of risk factors, and the vascular response to interventions.

PRINCIPLES OF ENDOTHELIAL FUNCTION TESTING

The importance of the endothelium was first recognized by its role in the regulation of vascular tone. This is achieved by production and release of vasoactive molecules (including nitric oxide [NO], prostacyclin and other vasoactive prostanoids, endothelium-derived hyperpolarizing factor [EDHF], endothelin-1 [ET-1], and free radicals) as well as the response to and modification of circulating vasoactive mediators (including angiotensin, bradykinin, and thrombin). These agents predominantly act locally, but may also have wider systemic influences acutely on vascular tone and chronically on arterial structure and remodeling. In addition to its vasodilator functions, NO has an important function in the maintenance of vascular health through its inhibitory effects on inflammation, thrombosis, and cell proliferation. When exposed to factors that "activate" the endothelium, a switch in the biology occurs from a NO-dominant quiescent phenotype to an activated phenotype in which "uncoupled" eNOS (endothelial Nitric Oxide Synthase) at generates reactive oxygen species in the absence of its cofactor tetrahydrobiopterin (superoxide) and or the substrate l-arginine (hydrogen peroxide). Indeed, most conventional and many novel risk factors activate common pathways within the endothelium thus resulting in the dysfunction of this system. This dual role of eNOS in both the maintenance of a basal quiescent status and activation of the endothelium places the enzyme at the center of endothelial and therefore arterial homeostasis. A number of changes occur with activation of the endothelium including expression of proinflammatory chemokines, ...

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