ReviewEndothelial microparticles as conveyors of information in atherosclerotic disease
Section snippets
Microparticles
Microparticles (MPs) are anucleoid submicron fragments (50 nm–1 μm diameter) of plasma membranes made up of oxidised phospholipids and specific proteins that represent the cells from which they originate. To date, MPs have been identified as particles released from vascular and blood-related cells such as endothelial cells, platelets, erythrocytes, leukocytes and smooth muscle cells, as demonstrated by their cell-specific surface proteins [1]. MPs were once referred to as ‘cell debris’ [2],
Microparticle release
A number of inflammatory or physical stimuli are able to induce cell activation or apoptosis via different signalling pathways resulting in disruption of lipid membrane asymmetry and cytoskeleton proteins [5]. In turn, this causes budding of the plasma membrane and release of MPs [6] (Fig. 1). Plasma membrane remodelling results from an imbalance between the cytoplasmic and outer plasma membrane aminophospholipids. Cytoplasmic aminophospholipids include phosphatidylserine (PS) and
Endothelial microparticle (EMP) composition and structure
MPs are complex vesicular structures, that consist of an inner and outer phospholipid bilayer containing membrane proteins and receptors [14], [15] (Fig. 1). The protein constituents of MPs are dependent on the cell type they were derived from, and the nature of the stimuli which cells are subjected to, as shown by proteomic analysis of MPs released in vitro from cultured cells [15].
EMPs have also been shown to contain mRNA and micro RNAs (miRs) [16], [17], [18]. MiRs are short non-coding RNAs
Detection of endothelial microparticles
MPs are detected using flow cytometry, a technique which separates cells or particles by their size, granularity and cell-surface antigens, using antibody-conjugated fluorophores [22]. MPs can be more accurately quantified by the addition of a known volume of size and density-specific fluorescently-labelled microbeads to the sample [23].
No single marker for EMPs exists, as many antigens are also present on a number of different cell sub-sets, therefore, for accurate identification a panel of
Atherosclerotic plaque formation
Atherosclerosis is a known chronic inflammatory disease characterised by atheromatous plaque deposition in the vascular bed. Plaque formation is a complex process largely driven by high blood cholesterol, endothelial activation and inflammation-induced vascular cell remodelling with deposition of extracellular matrix (ECM), lipid and calcification. Plaque instability and possible rupture may lead to athero-emboli triggering a major cardiovascular event, such as stroke or myocardial infarction.
Current biomarkers of cardiovascular disease
The risk of developing cardiovascular disease can be assessed by calculating a Framingham risk score, which takes into account, hypertension and high blood LDL, low HDL, and smoking. Typically, atherosclerosis remains undetected until a rupture or a reduction in blood flow results in a cardiovascular event, such as transient ischaemic attack, stroke or myocardial infarction.
There are many studies identifying new biomarkers associated with standard risk factors of cardiovascular disease [40]. A
Evidence of EMPs as a biomarker of atherosclerosis/cardiovascular disease
The vascular endothelium is of paramount importance in arterial wall integrity and blood flow regulation [43] and its activation can lead to cell membrane disruption by apoptosis and EMP release [25]. Our group has previously demonstrated that the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNF-α), stimulated significant release of EMPs from human aortic endothelial cells in vitro, an effect which was abrogated by the TNF-α-binding drug, certolizumab [24]. In patients with Systemic
Detrimental effect of EMPs in atherosclerotic disease
A number of studies have provided evidence on how MPs may be interacting with plaque initiation, formation and stability, although the exact mechanism remains largely unknown. Shear stress and turbulent flow, potential plaque-initiating factors, have been shown to stimulate endothelial cell apoptosis in endarterectomy plaques, which may favour EMP release. EMPs may also attenuate the bioavailability of endothelial nitric oxide, a well-known vasodilator, by stimulating the formation of free
A protective role for EMPs in atherosclerosis
Reports show that EMPs could play a protective role in disease by carrying proteins that possess anti-coagulant and anti-inflammatory properties. For example, Perez-Casal et al. demonstrated that EMPs were released when human endothelial cells were exposed to activated protein C (APC) [82]. Protein C has been shown to have an anti-coagulant and anti-inflammatory role since it can reduce the production of i) thrombin by inactivating factors Va & VIII, ii) tissue factor and iii) cytokines IL-1,
Summary
Despite the current understanding of atherosclerotic plaque development and rupture and the ominous outcome of thrombosis in asymptomatic patients, the question of what causes the transition from a stable to an unstable plaque has yet to be elucidated. Identifying a way of predicting patients' susceptibility to plaque rupture could have enormous cost-saving benefits in the clinic. Although research to explore the use of EMPs as biomarkers of disease has progressed substantially over the last
Funding
Manchester Royal Infirmary, Central Manchester University Hospitals NHS Foundation Trust (AA09299).
References (91)
- et al.
Microparticles, debris that hurts
J Am Coll Cardiol
(2008) - et al.
Plasmatic level of leukocyte-derived microparticles is associated with unstable plaque in asymptomatic patients with high-grade carotid stenosis
J Am Coll Cardiol
(2013) - et al.
Loss of membrane phospholipid asymmetry in platelets and red cells may be associated with calcium-induced shedding of plasma membrane and inhibition of aminophospholipid translocase
Biochim Biophys Acta
(1990) - et al.
CD40 ligand+ microparticles from human atherosclerotic plaques stimulate endothelial proliferation and angiogenesis a potential mechanism for intraplaque neovascularization
J Am Coll Cardiol
(2008) - et al.
Thrombin-induced endothelial microparticle generation: identification of a novel pathway involving ROCK-II activation by caspase-2
Blood
(2006) - et al.
Endothelial cells release phenotypically and quantitatively distinct microparticles in activation and apoptosis
Thromb Res
(2003) - et al.
Coronary heart disease alters intercellular communication by modifying microparticle-mediated microRNA transport
FEBS Lett
(2013) - et al.
Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA
Blood
(2007) - et al.
Activated platelets can deliver mRNA regulatory Ago2•microRNA complexes to endothelial cells via microparticles
Blood
(2013) - et al.
Microparticles are novel effectors of immunity
Curr Opin Pharmacol
(2013)
Basic principles of flow cytometry
Hematol/Oncol Clinics North Am
Vascular endothelium, hemodynamic forces, and atherogenesis
Am J Pathol
Inflammation in atherosclerosis: from pathophysiology to practice
J Am Coll Cardiol
Pathophysiology of atherosclerosis plaque progression
Heart Lung Circ
Thematic review series: the immune system and atherogenesis. Cytokines affecting endothelial and smooth muscle cells in vascular disease
J Lipid Res
Significance of a multiple biomarkers strategy including endothelial dysfunction to improve risk stratification for cardiovascular events in patients at high risk for coronary heart disease
J Am Coll Cardiol
Endothelial cells in physiology and in the pathophysiology of vascular disorders
Blood
Endothelial microparticles correlate with high-risk angiographic lesions in acute coronary syndromes
Int J Cardiol
Circulating endothelial microparticles in acute ischemic stroke: a link to severity, lesion volume and outcome
J Thromb Haemost JTH
Cell membrane microparticles in blood and blood products: potentially pathogenic agents and diagnostic markers
Transfus Med Rev
Microparticles: targets and tools in cardiovascular disease
Trends Pharmacol Sci
Effect of eprosartan on cytoplasmic free calcium mobilization, platelet activation, and microparticle formation in hypertension
Am J Hypertens
Digoxin use is associated with increased platelet and endothelial cell activation in patients with nonvalvular atrial fibrillation
Heart Rhythm
Microparticles of human atherosclerotic plaques enhance the shedding of the tumor necrosis factor-alpha converting enzyme/ADAM17 substrates, tumor necrosis factor and tumor necrosis factor receptor-1
Am J Pathol
Cellular origins and thrombogenic activity of microparticles isolated from human atherosclerotic plaques
J Am Coll Cardiol
Specific contribution of different phospholipid surfaces to the activation of prothrombin by the fully assembled prothrombinase
J Biol Chem
Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells
Cell
Atherosclerotic lesion progression changes lysophosphatidic acid homeostasis to favor its accumulation
Am J Pathol
Activated polymorphonuclear neutrophils disseminate anti-inflammatory microparticles by ectocytosis
Blood
Microparticles in cardiovascular diseases
Cardiovasc Res
Microvesicles as cell-cell messengers in cardiovascular diseases
Circ Res
Surface exposure of phosphatidylserine in pathological cells
Cell Mol Life Sci CMLS
Role of erythrocytes and platelets in the hypercoagulable status in polycythemia vera through phosphatidylserine exposure and microparticle generation
Thromb Haemost
Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I
Nat Cell Biol
Shear stress regulates endothelial microparticle release
Circ Res
Endothelial microparticle formation by angiotensin II is mediated via Ang II receptor type I/NADPH oxidase/Rho kinase pathways targeted to lipid rafts
Arterioscler Thromb Vasc Biol
Microvesicles: potential markers and mediators of endothelial dysfunction
Curr Opin Endocrinol Diabetes Obes
Proteomic analysis of malignant lymphocyte membrane microparticles using double ionization coverage optimization
Proteomics
Endothelial microparticle-mediated transfer of MicroRNA-126 promotes vascular endothelial cell repair via SPRED1 and is abrogated in glucose-damaged endothelial microparticles
Circulation
Microparticles from human atherosclerotic plaques promote endothelial ICAM-1-dependent monocyte adhesion and transendothelial migration
Circ Res
Suppression of inflammation reduces endothelial microparticles in active systemic lupus erythematosus
Ann Rheum Dis
Certolizumab pegol attenuates the pro-inflammatory state in endothelial cells in a manner that is atheroprotective
Clin Exp Rheumatol
The many faces of endothelial microparticles
Arterioscler Thromb Vasc Biol
Atherosclerosis
Nature
Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition
Proc Natl Acad Sci U S A
Cited by (0)
- 1
These authors contributed equally to this work.