Release of membrane vesicles, a process conserved in both prokaryotes and eukaryotes, represents an evolutionary link, and suggests essential functions of a dynamic extracellular vesicular compartment (including exosomes, microparticles or microvesicles and apoptotic bodies). Compelling evidence supports the significance of this compartment in a broad range of physiological and pathological processes. However, classification of membrane vesicles, protocols of their isolation and detection, molecular details of vesicular release, clearance and biological functions are still under intense investigation. Here, we give a comprehensive overview of extracellular vesicles. After discussing the technical pitfalls and potential artifacts of the rapidly emerging field, we compare results from meta-analyses of published proteomic studies on membrane vesicles. We also summarize clinical implications of membrane vesicles. Lessons from this compartment challenge current paradigms concerning the mechanisms of intercellular communication and immune regulation. Furthermore, its clinical implementation may open new perspectives in translational medicine both in diagnostics and therapy.

/pdf/membrane-vesicles-current-state-of-the-art-emerging-role-of-2orxx28bfa.pdf

Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles

https://www.kidney-international.org/article/S0085-2538(15)54664-4/pdf

Exosomes/microvesicles as a mechanism of cell-to-cell communication

In the past, endothelium was thought to be only a mechanical barrier. Today, endothelium is known to be a tissue regulating vascular tone, cell growth and the interaction between the leukocytes, thrombocytes and the vessel wall. It also synthesizes growth factors and thrombo-regulatory molecules and responds to physical and chemical signals. Even though the term "endothelial dysfunction" is generally used for deterioration of endothelium-dependent vasodilatation; the term also includes the abnormalities between endothelium and leukocytes, thrombocytes and regulatory molecules and conditions resulting in aberrant endothelium activation. Healthy endothelium is essential for cardiovascular control. Thus, it plays an important role in pathogenesis of many diseases and cardiovascular problems such as atherosclerosis, systemic and pulmonary hypertension, cardiomyopathies and vasculitides. The aim of this chapter is to explain endothelial dysfunction and the circulating molecules of endothelial cells as they become potential targets of therapeutic approach for hypertension. This chapter reviews the roles of endothelial dysfunction in hypertension by addressing (1) the nature of endothelial function, (2) mechanisms of endothelial dysfunction and its relationship with the diseases (3) also endothelial function testing (4) the role of endothelial dysfunction and hypertension and (4) the effects of antihypertensive therapeutic options on the endothelial dysfunction. In addition to these, the role of endothelial dysfunction in white coat hypertension has been discussed. The key connections between hypertension and endothelial dysfunction are vitally important for future studies to permit new interventions to be designed and released.

Endothelial Dysfunction and Hypertension.

Membrane vesicles released in the extracellular space are composed of a lipid bilayer enclosing soluble cytosolic material and nuclear components. Extracellular vesicles include apoptotic bodies, exosomes, and microvesicles (also known previously as microparticles). Originating from different subcellular compartments, the role of extracellular vesicles as regulators of transfer of biological information, acting locally and remotely, is now acknowledged. Circulating vesicles released from platelets, erythrocytes, leukocytes, and endothelial cells contain potential valuable biological information for biomarker discovery in primary and secondary prevention of coronary artery disease. Extracellular vesicles also accumulate in human atherosclerotic plaques, where they affect major biological pathways, including inflammation, proliferation, thrombosis, calcification, and vasoactive responses. Extracellular vesicles also recapitulate the beneficial effect of stem cells to treat cardiac consequences of acute myocardial infarction, and now emerge as an attractive alternative to cell therapy, opening new avenues to vectorize biological information to target tissues. Although interest in microvesicles in the cardiovascular field emerged about 2 decades ago, that for extracellular vesicles, in particular exosomes, started to unfold a decade ago, opening new research and therapeutic avenues. This Review summarizes current knowledge on the role of extracellular vesicles in coronary artery disease, and their emerging potential as biomarkers and therapeutic agents.

Extracellular vesicles in coronary artery disease

Microparticles are submicron vesicles shed from plasma membranes in response to cell activation, injury, and/or apoptosis. The measurement of the phospholipid content (mainly phosphatidylserine; PSer) of microparticles and the detection of proteins specific for the cells from which they are derived has allowed their quantification and characterization. Microparticles of various cellular origin (platelets, leukocytes, endothelial cells) are found in the plasma of healthy subjects, and their amount increases under pathological conditions. Endothelial microparticles (EMP) not only constitute an emerging marker of endothelial dysfunction, but are also considered to play a major biological role in inflammation, vascular injury, angiogenesis, and thrombosis. Although the mechanisms leading to their in vivo formation remain obscure, the release of EMP from cultured cells can be caused in vitro by a number of cytokines and apoptotic stimuli. Recent studies indicate that EMP are able to decrease nitric-oxide-dependent vasodilation, increase arterial stiffness, promote inflammation, and initiate thrombosis at their PSer-rich membrane, which highly co-expresses tissue factor. EMP are known to be elevated in acute coronary syndromes, in severe hypertension with end organ damage, and in thrombotic thrombocytopenic purpura, all conditions associated with endothelial injury and pro-thrombotic state. The release of EMP has also been associated with endothelial dysfunction of patients with multiple sclerosis and lupus anticoagulant. More recent studies have focused on the role of low shear stress leading to endothelial cell apoptosis and subsequent EMP release in end-stage renal disease. Improved knowledge of EMP composition, their biological effects, and the mechanisms leading to their clearance will probably open new therapeutic approaches in the treatment of atherothrombosis.

Endothelial microparticles in diseases

The molecular mechanisms by which extreme blood pressure elevation leads to vascular injury are not defined. To explore the hypothesis that activation of endothelium and platelets as manifested by increased concentrations of circulating endothelial microparticles and platelet microparticles could play a role in this target organ injury, we conducted a cross-sectional study of these markers in 3 groups: (1) untreated patients referred specifically for treatment of severe uncontrolled hypertension; (2) untreated patients with established mild hypertension; and (3) normotensive volunteer subjects. By ANOVA, endothelial (P=0.002) and platelet (P=0.01) microparticles were greatest in the severely hypertensive group. There was a significant correlation between both of these markers and blood pressure, even in the setting of multiple risk factors. Our results suggest that these markers may be useful and specific for pressure-induced endothelial and platelet activation in hypertension. Furthermore, because of the combined effects of endothelial and platelet microparticles on coagulation, leukocytes, and endothelium, it is possible that they may play a pathogenic role in mediating target organ injury in severe hypertension.

Effects of Severe Hypertension on Endothelial and Platelet Microparticles

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Effects of Severe Hypertension on Endothelial and Platelet Microparticles