Circulating markers of endothelial function in cardiovascular disease

Abstract

Endothelial dysfunction is a key event in cardiovascular disease. Measurement of endothelial dysfunction in vivo presents a major challenge, but has important implications since it may identify the clinical need for therapeutic intervention, specifically in primary prevention. Several biological markers have been used as indicators of endothelial dysfunction. The soluble adhesion molecules sICAM-1 and sVCAM-1 lack specificity and are increased in inflammatory processes. Both markers are increased in coronary artery disease. sICAM-1 level predicts the risk for cardiovascular disease or diabetes mellitus in healthy individuals. sE-selectin is specific for the endothelium and is increased in coronary artery disease and diabetes mellitus. sE-selectin is also associated with diabetic risk. The endothelium-specific marker, soluble thrombomodulin, is associated with severity of coronary artery disease, stroke or peripheral occlusive arterial disease and is not increased in healthy or asymptomatic subjects. Interestingly, thrombomodulin decreases during treatment of hypercholesterolemia or hyperhomocysteinemia. In contrast, von Willebrand factor is the best endothelial biomarker and predicts risk for ischemic heart disease or stroke.

Introduction

Endothelial function plays a central role in vascular homeostasis. The endothelial cell itself plays a key role in vascular diseases related to atherosclerosis. It is therefore useful to measure biological markers of vascular endothelial function in vivo because such markers might provide insight into the evolution and prognosis of vascular diseases.

The endothelium is a cell layer that regulates the exchange of water and small molecules as well as vasomotor tone, coagulation and fibrinolysis [1], [2]. Under physiological conditions, endothelial cells release a lot of molecules including nitric oxide (NO), prostacyclin (PGI2), EDHF (endothelium-derived hyperpolarizing factor), thrombomodulin and tissue-type plasminogen activator (tPA). These diverse factors facilitate vasodilation, fibrinolysis and inhibit platelet aggregation and coagulation [1], [2]. Endothelial dysfunction can be characterized as a change in normal endothelial phenotype, i.e., vasorelaxant, anticoagulant, antiplatelet and profibrinolytic, to one that is vasoconstrictive, procoagulant, platelet-activating and antifibrinolytic. Under these conditions, endothelial cells release lower levels of all the aforementioned molecules as well as increased levels of endothelin-1, angiotensin II, plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor [3], [4]. Normally, tissue factor is not present on the endothelial cell surface. During endothelial dysfunction, however, tissue factor becomes expressed as thrombin production is activated through the binding of factorVa/factorXa on surface of the endothelial cell [1], [2]. Upon activation by pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6), the endothelial expression of adhesion molecules such as ICAM-1, VCAM-1 and E-selectin increases, thus facilitating the migration of inflammatory cells and monocytes to the sub-endothelium.

Endothelial dysfunction is now considered as a key factor in atherosclerosis-related diseases and is present at all stages of atherosclerosis. The formation of plaques is characterized by the accumulation of inflammatory cells and oxidized low density lipoproteins (oxLDL) that reduce the intracellular NO and activate endothelial cells [5]. When activated, endothelial cells express increased amounts of adhesion molecules such as VCAM-1 and ICAM-1. These, in turn, stimulate monocyte adherence and increased levels of selectins that promote rolling of monocytes to the endothelial surface [1], [2]. The presence of high numbers of these inflammatory cells makes plaques more vulnerable to rupture and leads to myocardial infarction or acute coronary syndromes. Because endothelial dysfunction has been clinically demonstrated in coronary arteries of symptomatic patients [4], [6], [7], [8], specific and measurable markers of endothelial dysfunction in vivo are clearly needed. In order to accomplish this goal, two approaches have been proposed. One approach is to physically assess vasodilation in response to a stimulus [9]. This technique reflects the ability of the endothelium to secrete NO. The second approach is to measure biological markers. Candidate markers include circulating adhesion molecules (ICAM-1, VCAM-1, E-selectin), molecules that increase during endothelial damage (von Willebrand factor, soluble thrombomodulin) circulating endothelial cells) [10], [11] (Fig. 1). Such approaches are valid as long as endothelial dysfunction is considered systemic and not only a local phenomenon. This approach has been substantiated by studies that have correlated coronary vasomotor response to acetylcholine during catheterization and brachial artery flow-mediated dilation (FMD) [12], [13]. Another issue is the measurement of markers that have restricted expression to endothelial cells including E-selectin, von Willebrand factor and soluble thrombomodulin [3], [14], [15].

A correlation has been demonstrated between FMD, which reflects the ability of the endothelium to release NO, and the level of some biological markers of endothelial damage such as von Willebrand factor [16], [17]. This relationship is indicative of a global endothelium dysfunction including impaired vasorelaxation and endothelial activation and damage. Measuring endothelial function in vivo is potentially useful for evaluating the severity and prognosis of vascular disease, assessing the risk of vascular disease in asymptomatic patients, and for measuring drug efficacy. This review focuses on the biological markers of endothelial dysfunction and their potential usefulness in the setting of cardiovascular diseases. A search was conducted in the Pubmed Medline database with the following key-words (MeSh): [vascular diseases] AND [(endothelial cell) OR (von Willebrand factor) OR E-selectin OR (intercellular adhesion molecule-1) OR (vascular cell adhesion molecule-1)].