Extracellular Vesicles as Mediators in Atherosclerotic Cardiovascular Disease

Figures

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  Fig. 1. EV biogenesis and characteristics. EVs are classically suggested to either be formed intracellularly, assembled in MVBs and be released as “exosomes” or they may form by direct blebbing from the plasma membrane (“microvesicles”). Intersections with the endosomal pathway and autophagy exist. EVs inherit cell-derived (modified) membrane lipids and proteins, and cytosolic cargo, including nucleic acids and cell organelle components. ALIX, ALG-2 interacting protein X; ARRDC1, arrestin domain containing 1; CD, cluster of differentiation; ESCRT, endosomal sorting complex required for transport; EV, extracellular vesicle; MHC, major histocompatibility complex; MVB, multivesicular bodies; TSG101, tumor susceptibility gene 101 protein; VSP4A/B, vacuolar protein sorting 4 homolog A/B.

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  Fig. 2. EVs in atherosclerotic lesion progression and atherothrombosis. Homeostatic ECs under laminar flow are characterized by endothelial KLF2-expression and atheroprotective EC-derived EVs that carry miR-10a and miR-143/145. In contrast, various noxes and EVs derived from activated cells promote monocyte inflammation, adhesion and transmigration. EVs from stimulated cells promote M1-like differentiation or foam cell formation of monocytes and macrophages. Only erythrocyte-derived EVs are known to promote Mheme-like differentiation of monocytes. T-cell derived EVs and cholesterol-bearing EVs promote cholesterol uptake of macrophages, whereas VAT-derived EVs inhibit ABCA1- and ABCG1-mediated cholesterol efflux, and PVAT-EVs promote cholesterol efflux. Monocyte/macrophage and endothelial EVs mostly promote VSMC proliferation, migration and phenotype switching. Furthermore, EVs participate in macrophage apoptosis induction, in part by sustaining ERK1/2 phosphorylation, which ultimately leads to an increase of pro-apoptotic ceramides. Pro-inflammatory agents (oxLDL, IL-33) promote the release of procoagulant PS- and TF-bearing EVs from monocytes. EVs from monocytes and ECs promote…

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  Fig. 3. EV as inducers of endothelial activation and dysfunction. EVs released under the influence of ASCVD risk factors (nicotine/tobacco smoke, glucose, hyperlipidemia, …) or by otherwise stimulated cells (PAMPs: LPS; DAMPs: OxLDL, mitochondria, OSEs, …) activate endothelial cells (ROS increase, NF-κB pathway activation). This induces the release of pro-inflammatory cytokines (IL-6, IL-1β, TNF) and the expression of adhesion molecules (ICAM-1), leading to increased endothelial permeability and leukocyte transmigration and promoting endothelial cell death (apoptosis, pyroptosis). Various microRNAs (miR221/222, miR23a-3p, miR155), phospholipid-related molecules (arachidonic acid, PS, C16), cytokines (TNF, RANTES), oxidative stress-associated molecules (MDA/POVPC, ROS, NOX, SOX) and proteins relevant for signal transduction (Rap1, c-Src kinase) are involved in these processes. Inhibition of the release of EVs by activated cells (e.g., with GW4869) can mitigate EV-mediated pro-inflammatory intercellular communication. Natural IgMs neutralize the effect of OSE-bearing (MDA, POVPC) EVs. ASCVD, atherosclerotic cardiovascular disease; CD, cluster of differentiation; C16, C16 ceramide; c-Src…