Role of Extracellular Vesicles in the Pathogenesis of Vascular Damage

Abstract

Extracellular vesicles (EVs) are nanosized membrane-bound structures released by cells that are able to transfer nucleic acids, protein cargos, and metabolites to specific recipient cells, allowing cell-to-cell communications in an endocrine and paracrine manner. Endothelial, leukocyte, and platelet-derived EVs have emerged both as biomarkers and key effectors in the development and progression of different stages of vascular damage, from earliest alteration of endothelial function, to advanced atherosclerotic lesions and cardiovascular calcification. Under pathological conditions, circulating EVs promote endothelial dysfunction by impairing vasorelaxation and instigate vascular inflammation by increasing levels of adhesion molecules, reactive oxygen species, and proinflammatory cytokines. Platelets, endothelial cells, macrophages, and foam cells secrete EVs that regulate macrophage polarization and contribute to atherosclerotic plaque progression. Finally, under pathological stimuli, smooth muscle cells and macrophages secrete EVs that aggregate between collagen fibers and serve as nucleation sites for ectopic mineralization in the vessel wall, leading to formation of micro- and macrocalcification. In this review, we summarize the emerging evidence of the pathological role of EVs in vascular damage, highlighting the major findings from the most recent studies and discussing future perspectives in this research field.

Extracellular Vesicles, Inflammation, and Cardiovascular Disease

“…Smooth muscle cells, platelets, adipocytes, and endothelial cells, however, are equally important sources of EVs [ 18 ]. Regardless of their origin, EVs interact with immune cell mediators at all stages of disease progression ( Figure 2 ) [ 20 ].…”

“…The polarization of macrophages and the progression of macrophages to foam cells are important examples. Following LDL deposition in the subendothelial region, reactive oxygen species convert LDL to oxidized LDL, which, in turn, leads to monocyte-to-macrophage differentiation [ 20 , 29 ]. Further uptake of oxidized LDL by macrophages via scavenger receptors leads to the formation of lipid-containing foam cells.…”

“…Furthermore, these adipose-derived EVs polarize macrophages toward the classic pro-inflammatory M1 phenotype [ 31 ]. Similarly, endothelial EVs have the capacity to polarize macrophages, either toward the M1 phenotype or the anti-inflammatory M2 phenotype, depending on environmental stimuli [ 20 ]. Endothelial cells exposed to oxidized LDL secrete EVs containing metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), which promotes M2 polarization [ 32 ].…”

“…Smooth-muscle-cell-derived EVs are equally important in promoting microcalcification. The reader is referred elsewhere for a thorough review of these mechanisms [ 20 ]. In conclusion, the interplay between EVs derived from leukocytes, platelets, endothelial cells, adipocytes, and smooth muscle cells is central to the pathogenesis of atherosclerosis, and mechanistic insights into this interplay have important therapeutic implications.…”

Emerging Roles of Extracellular Vesicle-Delivered Circular RNAs in Atherosclerosis

“…EV is associated with the initiation and progression of vascular calcification. Under pathological stimulation, macrophages and SMCs secrete EVs, which accumulate between collagen fibres and act as nucleation sites for ectopic mineralization of vascular walls, causing the formation of microcalcifications and macrocalcifications ( Buffolo et al, 2022 ). It was reported that SMC-derived EVs initiate microcalcification in atherosclerotic plaques.…”