[Frontiers in Bioscience 9, 1118-1135, May 1, 2004]

ENDOTHELIAL MICROPARTICLES AS MARKERS OF ENDOTHELIAL DYSFUNCTION

Lawrence L Horstman, Wenche Jy, Joaquin J. Jimenez and Yeon S. Ahn

Wallace Coulter Platelet Laboratory, Division of Hematology/Oncology, Department of Medicine, University of Miami, School of Medicine

TABLE OF CONTENTS

1. Abstract
2. Background: Review of previous markers of endothelial injury
2.1. Foreword
2.2. Circulating endothelial cells
2.2.1. Circulating endothelial progenitor cells (CEPC)
2.3. Soluble markers of endothelial injury
3. History and methods of endothelial microparticle analysis
3.1. What are endothelial microparticles?
3.2. Historical perspective
3.3. Assay methods
3.3.1. General flow cytometric
3.3.2. Enzyme-linked immunoassay methods for EMP
3.3.3. Validation of detection specificity
3.3.4. Total endothelial microparticles
3.3.5. Endothelial microparticles and other microparticles in normal controls
4. EMP studies in vitro
4.1. Heterogeneity of endothelial microparticles
4.2. Endothelial microparticle analysis distinguishes apoptosis from activation
4.3. Electron micrographs of endothelial microparticles
4.4. Plasma from patients induces the release of endothelial microparticles
4.5. Plasminogen activator inhibitor-1 induces endothelial microparticles
4.6. Mechanism of generation of endothelial microparticles
4.7. Potential functional roles of endothelial microparticles
4.7.1. Modulation of leukocyte function
4.7.2. Procoagulant activity
4.7.3. Anti-coagulant function
4.7.4. Decoy theory
4.7.5. Expulsion of noxious agents
4.7.6. Protective function
5. EMP in clinical studies
5.1. Introduction
5.2. Patients with lupus anticoagulant
5.3. Thrombotic thrombocytopenic purpura
5.3.1.EMP and vWF
5.4. Multiple Sclerosis
5.4.1. EMP-leukocyte conjugates in MS
5.4.2. Transendothelial migration of leukocytes through BBB
5.5. Acute coronary syndromes
5.6. Hypertension
5.7. Preeclampsia
5.8. Diabetes
5.9. Paroxysmal nocturnal hemoglobinuria, sickle cell crisis
5.10. Work in progress
5.10.1. Metabolic syndrome
5.10.2. Hyperlipidemia
5.10.3. Sepsis
6. Perspective
7. Acknowledgement
8. References

1. ABSTRACT

Endothelial microparticles (EMP) are small vesicles released from disturbed endothelial cells (EC). Owing to the central importance of EC injury in thrombotic and inflammatory conditions, assay of EMP as a marker of EC disturbance has come under intensive development by several laboratories. The review begins with established markers of EC injury, commonly soluble markers such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, von Willebrand factor (vWF), etc., pointing out that many of these are in fact mixtures of true soluble molecules with membrane-bound forms, i.e., EMP. Assays of EMP from different labs are reviewed and standardization of assay is recommended. EMP are heterogeneous: those released in activation vs. apoptosis are distinctive in phenotypic markers and procoagulant properties. Application of EMP phenotype analysis can distinguish EC state of activation from apoptosis. Some EMP carry functional vWF with properties different from soluble vWF. Certain EMP bind to and activate monocytes; EMP-monocyte conjugates were found to be a marker of inflammatory disease such as multiple sclerosis (MS), and to enhance transendothelial migration of leukocytes in vitro. Clinical studies have revealed elevated plasma levels of EMP in lupus anticoagulant (LA), multiple sclerosis (MS), thrombotic thrombocytopenic purpura (TTP), coronary artery disease (CAD), hypertension, preeclampsia, and diabetes. Further refinement of EMP assay could open new windows for evaluating and monitoring endothelial injury in thrombotic and inflammatory disorders.