Extracellular vesicle signalling in atherosclerosis

Abstract

Atherosclerosis is a major cardiovascular disease and in 2016, the World Health Organisation (WHO) estimated 17.5 million global deaths, corresponding to 31% of all global deaths, were driven by inflammation and deposition of lipids into the arterial wall. This leads to the development of plaques which narrow the vessel lumen, particularly in the coronary and carotid arteries. Atherosclerotic plaques can become unstable and rupture, leading to myocardial infarction or stroke. Extracellular vesicles (EVs) are a heterogeneous population of vesicles secreted from cells with a wide range of biological functions. EVs participate in cell-cell communication and signalling via transport of cargo including enzymes, DNA, RNA and microRNA in both physiological and patholophysiological settings. EVs are present in atherosclerotic plaques and have been implicated in cellular signalling processes in atherosclerosis development, including immune responses, inflammation, cell proliferation and migration, cell death and vascular remodeling during progression of the disease. In this review, we summarise the current knowledge regarding EV signalling in atherosclerosis progression and the potential of utilising EV signatures as biomarkers of disease.

Keywords: Atherosclerosis; Coronary artery disease (CAD); Extracellular vesicles (EVs); microRNA (miRNA).

Fig. 1

Atherosclerotic plaque formation. (A) Lipoprotein retention to the vascular wall and disturbed flow activate the expression of adhesion molecules (vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1)) on endothelium with subsequent monocyte recruitment to the vessel wall. Monocytes differentiate to macrophages, take up oxidised low density lipoprotein (oxLDL), form foam cells and a pro-inflammatory reaction is activated. Vascular modifications result in SMC migration to the subendothelial space. (B) A stable plaque is formed of a lipid core and the accumulation of necrotic cells as foam cells undergo apoptosis and necrosis. SMC secrete macromolecules like collagen, elastin, fibronectin and extracellular matrix facilitating fibrous cap formation. (C) Thin fibrous cap results in a vulnerable plaque prone to rupture and secondary complications like thrombus formation. Macrophage proteolytic activity with matrix metalloproteinases (MMPs) being the main proteolytic enzymes has been associated with plaque rupture.

Fig. 2

EV Biogenesis. EV classification is based upon the particle size and their biogenesis. Apoptotic bodies are large vesicles and are formed after blebbing of the plasma membrane. Microvesicles are a product of outward budding of the plasma membrane. Exosomes are smaller endosomal vesicles and released upon fusion of the MVBs with the plasma membrane. The figure was generated with Blender 2.8 which is released for free use under a GNU General Public License (GPL).

Fig. 3

EV signalling in vascular inflammation and atherosclerosis. Brief schematic representation of EVs and their roles in the steps of atherosclerotic lesion progression. (A) During fatty streak formation, EC-derived EVs promote endothelial ICAM-1, VCAM-1 expression, reduction of NO production, oxLDL uptake by macrophages and macrophage migration. Monocyte-derived EVs induce vascular inflammation (expression of IL-6, IL-1β), upregulation of adhesion molecules in ECs (ICAM-1, VCAM-1 and E-selectin) and vascular cell death. Foam cell-EVs and platelet-EVs can induce SMC proliferation and migration, aggravating the progression of the disease. Crosstalk between cells is fundamental; SMC-EVs can promote EC migration and via miRNA transfer promote tight junction destruction. (B) Dead cells accumulate in the plaque's necrotic core. Platelet, endothelial, dendritic and monocytic-derived EVs encapsulate cell death related proteases: caspase-1 and caspase-3 that can induce macrophage apoptosis. Monocyte-EVs can promote SMC death via caspase-1 and participate in formation of the atherosclerotic plaque. (C) Weakening of the fibrous cap is the main cause of plaque rupture. EVs from various sources (macrophage, neutrophil, endothelial) encapsulate MMPs and may degrade extracellular matrix and destabilize the plaque. Platelet and monocyte derived EVs can also enhance thrombus formation.