L70	The significance of membrane microparticles in vascular pathophysiology and intercellular communication.
1J-M.Freyssinet, 2J-M.Freyssinet
1Unité 143 Inserm - Hôpital de Bicêtre, Le Kremlin-Bicêtre, FR; 2Institut d'Hématologie & Immunologie - Faculté de Médecine - Université Louis Pasteur, Strasbourg, FR.

Membrane microparticles (MPs), also referred to as microvesicles, are submicron fragments shed from the plasma membrane of stimulated or apoptotic cells. MPs constitute relevant hallmarks of cellular activation or damage, whilst the cells they stem from remain sequestered in tissues or are promptly submitted to phagocytic clearance. MPs participate in transcellular exchange of biological information, and can therefore be viewed a true disseminated “storage pool” of bioactive effectors. They carry blood-borne tissue factor (TF), the main cellular initiator of the clotting cascade, and procoagulant phosphatidylserine (PS), pro-inflammatory or apoptogenic mediators. Increasing evidences of integrated loops involving dynamic exchanges and transfer events through multiple MP-cell interactions explain how MPs can acquire a deleterious potential towards the vascular function, with a central role for the P-selectin pathway in the amplification of the generation of MPs harbouring TF. MPs can therefore participate in a sort of “resonance” process leading to an acute event. Detectable in the peripheral blood of normal individuals, MPs are elevated in clinical situations where the atherothrombotic risk is increased, including the metabolic syndrome and diabetes. Owing to platelet responsiveness under most pathophysiologic conditions, platelet-derived MPs appear the main procoagulant circulating species and perhaps the main source of blood-borne TF, leukocytic or endothelial origins being less represented, which does not however rule out a particular significance when also elevated. In fact, due to the plasticity of the lateral organization of the plasma membrane into raft domains known to segregate particular proteins and lipid species, a given stimulus can be expected to elicit a “private” response resulting in an inclusive and exclusive sorting, a timely example being the transfer of TF from monocytic rafts to platelets. This explains how MPs of a same cellular origin may have different protein and lipid compositions. Because they are pathogenic markers, MPs can actually be considered true pharmacological targets in the therapeutic management of atherothrombosis. This requires a better knowledge of the relationships between their specific characteristics conferred by the tissue and nature of the stimulation at their origin and their associated noxious functions. In a number of studies, MPs were produced in vitro from stimulated cultured cells, and assessed with respect to associated toxicity, but such MPs are far to represent the much wider counterpart categories detected in vivo. Hence, it has to be realised that only patients “can” generate objectively relevant MPs. In this respect, we and others have precisely reported that MPs from patients with cardiovascular disorders can be detrimental towards endothelial/vascular functions through different mechanisms, including induction of an inflammatory response. At the opposite, a challenging issue is that of possible beneficial effects of MPs when carrying remote-signalling entities involved in regenerative processes.

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