Extracellular Vesicles: Versatile Nanomediators, Potential Biomarkers and Therapeutic Agents in Atherosclerosis and COVID-19-Related Thrombosis

Figures

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  Figure 1. Diagram representing the classification, biogenesis, molecular content and interactions with target cells of extracellular vesicle (EVs). Exosomes originate from the early sorting endosome (ESE), which turn sequentially into late sorting endosome (LSE), and multivesicular bodies (MVBs), whose intraluminal vesicles (ILVs) are exocytosed upon fusion and inward invagination of the plasmalemma. Ectosomes, also named microparticles (MPs) or microvesicles (MVs) are formed upon plasma membrane budding with phosphatidyl serine (PS) on the outer membrane surface. Apoptotic bodies (ApoBDs are membrane-derived large vesicles originating from apoptotic cells with PS as surface marker). (RME: receptor mediated endocytosis).

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  Figure 2. Diagram representing the arbitrary consecutive stages in the development of atherosclerotic plaques in arterial lesion-prone areas. Stage I. Endothelial cell (EC) activation/modulation of constitutive functions. The initial stage in atheroma formation is the accumulation within the plasma of oxidatively modified lipoproteins (MLp) that induce EC activation and increased transcytosis of MLp, i.e., their housing in the subendothelium where they interact with the components of the extracellular matrix (ECM). EC switch to a secretory phenotype that produces an excess of hyperplasic basal lamina. Stage II. EC dysfunction. Affected luminally by the alterations of plasma homoeostasis and abluminally by the accrual of MLp, the EC initiate an inflammatory process (i.e., the expression of new or more cell adhesion molecules, cytokines and chemokines) that attract immune cells such as neutrophils (PMN) which interact with platelets (Pl) and assist leucocyte migration. Stage III. Commencement of a robust inflammatory reaction. The recruitment of blood monocytes (Mon) and T lymphocytes (T-LY), diapedesis of Mon into the intima, where they become activated macrophages (Mac), expressing…

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  Figure 3. Thrombosis is a consequence of reduced fibrinolysis and thrombolysis processes, and the subsequent dramatic increase in platelet aggregation due to an imbalance of endothelial and platelet circulating mediators. The figure shows an electron-micrograph of an arteriole exhibiting activated endothelial cells (EC), and the upregulated and downregulated mediators (arrows) that lead to thrombosis. An increase in plasma von Willebrand factor (vWF) that enhances platelet adhesivity, plasmin activator inhibitor (PAI-1) that inhibits tPA and uPA, and thromboxane A2 that activates the platelets, leads to platelet aggregation and the formation of thrombus. Concomitantly, thrombus formation is due to a decrease in plasma prostacyclin (PGI2) that controls platelet activation, tissue plasmin activator (tPA) that, together with urokinase plasminogen activator (uPA), breaks down fibrin into fibrin degradation products, and antithrombin (an active anticoagulant). Ultimately, the increase in tissue factor (TF) and fibrinogen, and the decrease of thrombomodulin, create a prothrombotic milieu by initiating the coagulation cascade, platelet aggregation and the formation of thrombus.