Extracellular vesicles in atherothrombosis and cardiovascular disease: Friends and foes

Highlights

• Extracellular vesicles (EV) range 30–1000 nm in diameter, and are released from almost all cell types through several pathways.

• EV are pro- or anti-atherothrombotic depending on their content, the cell of origin, and their biogenic context.

• EV actively participate in every step of atherosclerosis, and in thrombus formation leading to a cardiovascular event.

• EV may have protective biological functions in atherothrombosis and cardiac repair.

Abstract

Extracellular vesicles (EV, exosomes and microvesicles -MV-) are 30–1000 nm particles surrounded by a phospholipid bilayer membrane that are released from almost all cell types through several pathways. EV encapsulate bioactive molecules, and the molecular cargo is determined by the trigger stimulating its release, reflecting its cell origin and biological functions.

This review is primarily focused on the latest evidence of the roles of EV, released from cells involved in the different stages of atherothrombosis. The potential translation of this information to the clinical arena is also discussed.

EV can have both pro- and anti-atherothrombotic effects depending on several factors, such as the type of vesicle (MV/exosome), its molecular cargo, its cell of origin, and the context in which are generated, i.e., the stimulus triggering its release. In fact, EV actively participate in every step of atherosclerosis onset and progression, and also in thrombus formation leading to a major adverse cardiovascular event. Moreover, EV have a determinant role in fibrous cap stability, thus determining the propensity of the plaque to rupture. On the other hand, and again, conditioned by the context and stimulus instigating its secretion, some EV may have protective biological functions, perhaps as a compensatory mechanism or even with reparative or regenerative potential. Therefore, the study of the implication of EV in atherothrombosis might be of relevance to unveil new therapeutic targets, vectors and biomarkers of cardiovascular disease (CVD).

Introduction

In the last decade, extracellular vesicles (EV) have been recognised as biological entities providing new mechanisms of intercellular communication in the physiology, and in the pathophysiology of various diseases. EV are a composite of heterogeneous particles ranging 30–5000 nm in diameter, surrounded by a phospholipid bilayer, which are released into the extracellular space by almost all cell types. EV encapsulate bioactive molecules (such as lipids, proteins, RNA and metabolites), which reflect the cellular origin and the stimulus that triggered the release, and determines its biological function [1]. According to biogenesis and size, EV can be classified into three main subtypes: exosomes (30–150 nm), microvesicles (MV; 100–1000 nm, formerly called microparticles in the cardiovascular field), and apoptotic bodies (1–5 μm). Exosomes are intraluminal vesicles within multivesicular bodies generated by the endosomal sorting complexes machinery; MV are blebs generated by the cell membrane budding, and apoptotic bodies are generated as a consequence of the membrane disintegration [2]. Therefore, EV are heterogeneous in size, composition (both of the membrane and intravesicle contents), biogenesis, origin, and biological function [3]. EV are present in many biological fluids, and may exert their function by targeting specific cells to which their cargo is delivered by different trafficking routes [4]. Hence, EV are being the object of intensive research in several pathologies such as cancer, cardiovascular disease (CVD) and cardiac repair, and also metabolic, neurological, immune, and infectious diseases [5]. Taking into consideration that the current main body of research is sustained in the study of EV up to 1 μm in diameter, this review is focused on exosomes and MV, and the term EV will be exclusively referred to these two types of vesicles. To review the roles of apoptotic bodies in atherosclerosis please refer to Refs. [[5], [6], [7], [8]].

The principal underlying cause of CVD is atherosclerosis. Thus, the study of the implication of EV in atherosclerosis onset and progression might be of relevance to unveil new therapeutic targets and biomarkers of CVD. Despite the COVID-19 pandemics, CVD still remains the main cause of mortality worldwide, accounting for one-third of the total deaths [9]. Atherosclerosis is a chronic and progressive oxidative and low-grade inflammatory disease initiated by excessive lipid deposition in the artery wall (atherosclerotic plaques), progressively narrowing the artery [10]. This accumulation of lipids unleashes endothelial dysfunction, which in turn provokes leukocyte recruitment to the lesion sites (plaques). In an attempt to remove this excessive lipid deposition, macrophages end up shifting to foam cells, and simultaneously, vascular smooth muscle cells (VSMC) switch to a synthetic and proliferative phenotype, exacerbating the lesion. As the plaque grows, a necrotic core is formed, and vasa vasorum neoangiogenesis occurs as a compensation mechanism. In a further stage, calcification takes place. However, the atherosclerotic lesion eventually bursts, favouring a thrombus formation that occludes the artery, leading to a major adverse cardiovascular event (MACE).

Considering the involvement of a large variety of cell types in the atherosclerotic process, this review primarily focuses on the latest evidence of the roles of EV (exosomes and MV), released from cells involved in the different stages of atherothrombosis. As such, the potential translation of this information to the clinical arena is also discussed.