Invited critical reviewCirculating markers of endothelial function in cardiovascular disease
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)].
Section snippets
von Willebrand factor
von Willebrand factor (vWF) is an endothelial ligand for platelet glycoproteins and is endothelium-specific. vWF plays a vital role in mediating platelet adhesion to damaged arterial walls [18]. When endothelial cells are injured, vWF is released from endothelial Weibel–Palade bodies. vWF, considered a gold standard in the measurement of endothelial damage, is increased in cardiovascular diseases [19]. Plasma vWF can be measured by enzyme-linked immunosorbent assay (ELISA). The concentration of
Conclusion
Several approaches can be used to measure endothelial function, a major player in vascular diseases. Flow-mediated dilation measured by ultrasound reflects the endothelial production of NO, but is difficult to standardize and use in clinical practice. Several biological markers reflect activation of the endothelium, either specifically (sE-selectin) or non-specifically (sVCAM-1, sICAM-1). sTM and vWF are potentially better markers because they reflect endothelial damage. Other markers such as
References (211)
Endothelial cell function and thrombosis
Baillieres Best Pract Res Clin Haematol
(1999)Endothelial dysfunction: does it matter? Is it reversible?
J Am Coll Cardiol
(1997)- et al.
The binding of oxidized low density lipoprotein (ox-LDL) to ox-LDL receptor-1 reduces the intracellular concentration of nitric oxide in endothelial cells through an increased production of superoxide
J Biol Chem
(2001) - et al.
Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis
Lancet
(1992) - et al.
Letter: factor-VIII complex and endothelial damage
Lancet
(1975) - et al.
Endothelium-dependent flow-mediated vasodilation in coronary and brachial arteries in suspected coronary artery disease
Am J Cardiol
(1998) - et al.
Systemic nature of endothelial dysfunction in atherosclerosis
Am J Cardiol
(1995) - et al.
Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity
Blood
(2004) - et al.
Endothelial function, platelet activation and coagulation in lower limb occlusive arterial disease during treadmill exercise: correlations with transcutaneous oxygen pressure
Thromb Res
(2000) - et al.
von Willebrand factor and soluble E-selectin in the prediction of cardiovascular disease progression in hyperlipidaemia
Atherosclerosis
(1997)
Endothelial dysfunction during acute methionine load in hyperhomocysteinaemic patients
Atherosclerosis
Soluble thrombomodulin in hypercholesterolaemic patients
Lancet
Effects of rosiglitazone on endothelial function in men with coronary artery disease without diabetes mellitus
Am J Cardiol
The effects of rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, on markers of endothelial cell activation, C-reactive protein, and fibrinogen levels in non-diabetic coronary artery disease patients
J Am Coll Cardiol
Short-term high-dose folic acid does not alter markers of endothelial cell damage in patients with coronary heart disease
Int J Cardiol
A randomized comparison of the effects of aspirin and clopidogrel on thrombotic risk factors and C-reactive protein following myocardial infarction: the CADET trial
J Thromb Haemost
Genetic variation in the human thrombomodulin promoter locus and prognosis after acute coronary syndrome
Thromb Res
Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) Study: a case–cohort study
Lancet
Cross-sectional association of soluble thrombomodulin with mild peripheral artery disease; the ARIC study. Atherosclerosis Risk in Communities
Atherosclerosis
Levels of plasma thrombomodulin are increased in atheromatous arterial disease
Thromb Res
Relationship between endothelial cell markers and arterial stenosis in peripheral and carotid artery disease
Thromb Res
Circulating cell adhesion molecules and endothelial markers before and after transluminal angioplasty in peripheral arterial occlusive disease
Atherosclerosis
Acute rejection before cytomegalovirus infection enhances von Willebrand factor and soluble VCAM-1 in blood
Kidney Int
Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells
Blood
Selectins and their ligands: current concepts and controversies
Blood
Soluble forms of E-selectin, ICAM-1 and VCAM-1 are present in the supernatants of cytokine activated cultured endothelial cells
Biochem Biophys Res Commun
Evidence of prolonged inflammation in unstable angina and non-Q wave myocardial infarction
J Am Coll Cardiol
Increased plasma level of soluble E-selectin in acute myocardial infarction
Am Heart J
Elevated levels of circulating soluble adhesion molecules in peripheral blood of patients with unstable angina
Am J Cardiol
Increased plasma levels of soluble selectins in patients with unstable angina
Int J Cardiol
Circulating intercellular adhesion molecule-1 and E-selectin in patients with acute coronary syndrome
Chest
Serum levels of selected adhesion molecules in patients with coronary artery disease
Int J Cardiol
Elevation of soluble adhesion molecules is associated with the severity of myocardial damage in acute myocardial infarction
Am J Cardiol
Levels of expression of P-selectin, E-selectin, and intercellular adhesion molecule-1 in coronary atherectomy specimens from patients with stable and unstable angina pectoris
Am J Cardiol
Prediction of recurrent events by D-dimer and inflammatory markers in patients with normal cardiac troponin I (PREDICT) study
Am Heart J
Endothelial cell functions
J Cell Physiol
A reliable marker of endothelial cell dysfunction: does it exist?
Br J Haematol
New markers of inflammation and endothelial cell activation: Part I
Circulation
Endothelial function, inflammation, and prognosis in cardiovascular disease
Am J Med
Endothelial dysfunction: a marker of atherosclerotic risk
Arterioscler Thromb Vasc Biol
Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells
Thromb Haemost
Vascular cell adhesion molecule-1 and smooth muscle cell activation during atherogenesis
J Clin Invest
Various cell types in human atherosclerotic lesions express ICAM-1. Further immunocytochemical and immunochemical studies employing monoclonal antibody 10F3
Am J Pathol
Endothelial dysfunction and damage in congestive heart failure: relation of flow-mediated dilation to circulating endothelial cells, plasma indexes of endothelial damage, and brain natriuretic peptide
Circulation
Factor VIII and von Willebrand factor
Thromb Haemost
von Willebrand factor: a marker of endothelial dysfunction in vascular disorders?
Cardiovasc Res
Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study
Thromb Haemost
Factor VIII, von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Heart study
Br J Haematol
von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn study
Arterioscler Thromb Vasc Biol
Factor VIII, ABO blood group and the incidence of ischaemic heart disease
Br J Haematol
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