Role of microparticles in atherothrombosis.

Cell activation or apoptosis leads to plasma membrane blebbing and microparticle (MP) release in the extracellular space. MPs are submicron membrane vesicles which express a panel of phospholipids and proteins specific of the cells they are derived from. Exposure of negatively charged phospholipids and tissue factor confers a procoagulant potential to MPs. MPs accumulate in the lipid core of the atherosclertotic plaque and is a major determinant of its thrombogenecity. Elevation of plasma MPs levels, particularly those of endothelial origin, reflects cellular injury and is considered now as a surrogate marker of vascular dysfunction. Thus, MPs can be seen as triggers of a vicious circle for they promote prothrombogenic and pro-inflammatory responses as well as cellular dysfunction within the vascular compartment. A better knowledge of MP composition and biological effects as well as the mechanisms leading to their clearance will probably open new therapeutic approaches in the treatment of atherothrombosis.

Microparticles and type 2 diabetes.

Cell activation or apoptosis leads to plasma membrane blebbing and microparticles (MPs) release in the extracellular space. MPs are submicron membrane vesicles, which harbour a panel of oxidized phospholipids and proteins specific to the cells they derived from. MPs are found in the circulating blood of healthy volunteers. MPs levels are increased in many diseases, including cardiovascular diseases with high thrombotic risk. Exposure of negatively charged phospholipids and tissue factor confers a procoagulant potential to MPs. Elevation of plasma MPs levels, particularly those of endothelial origin, reflects cellular injury and appears now as a surrogate marker of vascular dysfunction. Recent studies demonstrate an elevation of circulating levels of MPs in diabetes. MPs could also be involved in the development of vascular complications in diabetes for they stimulate pro-inflammatory responses in target cells and promote thrombosis, endothelial dysfunction and angiogenesis. Thus, these studies provide new insight in the pathogenesis and treatment of vascular complications of diabetes.

[Circulating endothelial microparticles: a new marker of vascular injury]. / Microparticules endothéliales circulantes: un nouveau marqueur du dysfonctionnement vasculaire.

Cell activation or apoptosis leads to plasma membrane blebbing and microparticles (MPs) release. MPs are submicron membrane vesicles expressing a panel of oxidized phospholipids and proteins specific of the cells they originate from. Exposure of negatively charged phospholipids and tissue factor confers a procoagulant potential to MPs. Increases in plasma MPs levels, particularly those of endothelial origin, reflects cellular injury and appears now as a surrogate marker of vascular dysfunction. MPs are also biologically active and stimulate pro-inflammatory responses in target cells. Thus, MPs can promote a prothrombogenic and pro-inflammatory vicious circle leading to vascular dysfunction. A better understanding of MPs composition, as well as their effects and the mechanisms leading to their clearance will likely open new therapeutic approaches in the treatment and the prognosis of cardiovascular diseases.

Targeting soluble CD146 with a neutralizing antibody inhibits vascularization, growth and survival of CD146-positive tumors.

CD146 (MUC-18, MCAM) expression on cancer cells correlates with cancer progression and a bad prognosis in several tumors, including melanoma and pancreatic tumors. Deciphering the mechanism mediating the CD146 role in cancer is essential for generating new therapeutic strategies. We found that CD146 expression in cancer cells is associated with a secretion of soluble CD146 (sCD146) that constitutes an active player in tumor development. Indeed, sCD146 induces the overexpression of its binding protein, angiomotin, on both endothelial and cancer cells and promotes both paracrine effects on angiogenesis and autocrine effects on cancer cells proliferation and survival. These last effects are mediated in part through the induction and phosphorylation of c-myc in cancer cells. In mice models xenografted with human CD146-positive melanoma or pancreatic cancer cells, administration of a novel monoclonal antibody specifically targeting sCD146, but not its membrane form, successfully suppresses tumor vascularization and growth. Our findings demonstrate that sCD146 secreted by CD146-positive tumors mediates important pro-angiogenic and pro-tumoral effects. Targeting sCD146 with a novel neutralizing antibody could thus constitute an innovative therapeutic strategy for the treatment of CD146-positive tumors.

Revisited role of microparticles in arterial and venous thrombosis.

Microparticles (MPs) represent a heterogeneous population of submicronic vesicles that are released in response to cell activation or apoptosis. MPs harbor a large repertoire of cell surface receptors and mRNA and biological activities representative of their parent cells and related to their involvement in many biological functions. Although MP generation is a physiological response, a dramatic increase in circulating MPs is detectable in a variety of thrombosis-associated disorders compared with healthy individuals. In this review, we will discuss a new vision of MPs as complex and ambivalent structures that express both activators and inhibitors of coagulation but also convey fibrinolytic properties. After summarizing our current knowledge about the role of MPs in venous and arterial thrombosis, this review will explore how this new vision of MPs influences their definition as emergent biomarkers in thrombotic diseases. Among the studies that have aimed to establish a link between thrombosis and MPs, a few studies have demonstrated a predictive value of MPs. So far, it is unclear whether this limited causative association is the result of current technical concerns and limited standardization or has to be integrated into a more complex vision of the role of MPs as key systems for regulating the balance between coagulation and fibrinolysis.

[Cell-derived microparticules: key players at the crossroad between inflammation and thrombosis]. / Rôle des microparticules cellulaires à l'interface des réponses prothrombotiques et inflammatoires.

Cell-derived microparticles are complex vesicular structures that can be shedded by activated or apoptotic endothelial cells. Cell-derived microparticles are composed of a phospholipid bilayer that exposes transmembrane proteins and receptors and encloses cytosolic components such as enzymes, transcription factors and mRNA derived from their parent cells. Thus, they behave as biological conveyors playing a key role in the tuning of vascular homeostasis. This review will address the potential of microparticles as efficient vectors of biological activities in pathologies. Based on the model of endothelial vesiculation, the first part of this review will develop the contribution of endothelial microparticles to coagulation inflammation and angiogenesis and their role in vascular disorders. The second part will be focused on the multifaceted impact of cell-derived microparticles present in blood products and its relevance to transfusion medicine.