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.

Keywords: atherosclerosis; endothelial dysfunction; extracellular vesicle vascular inflammation; hypertension; vascular calcification.

Figure 1.. Pathological role of extracellular vesicles in different stages of vascular damage

Extracellular vesicles (EVs) released by different cells under several pathological conditions mediates initiation and propagation of vascular damage, from endothelial dysfunction to vascular inflammation, atherosclerosis, alteration of extracellular matrix composition and vascular calcification. NO=nitric oxide, ROS=reactive oxygen species, Rap1=ras-associated protein-1, SMC=smooth muscle cell, LDL=low-density lipoproteins, ERK=extracellular signal-regulated kinases, NFκB=nuclear factor kappa-light-chain-enhancer of activated B cells, TNAP= tissue nonspecific alkaline phosphatase, MGP=matrix Gla protein. Some illustrations of the Figure were prepared using Motifolio drawing toolkit.

Figure 2.. Extracellular vesicles biogenesis and role in the development of cardiovascular calcification

Extracellular vesicles (EVs) are released by cells by two mechanisms: direct budding or fission of the plasma membrane, generating microvesicles; multivesicular bodies generation of intracellular vesicles and their release in the extracellular space through fusion with the plasma membrane, generating exosomes. EVs and microvesicles drive calcification process in the arterial walls through multiple pathways, including tissue non-specific alkaline phosphatase (TNAP) generation of free phosphate, sortilin-mediated loading of TNAP into EVs, annexin A1 tethering of EVs and S100A9 enhancement of EV-mediated ectopic calcification process. Some illustrations of the Figure were prepared using Motifolio drawing toolkit.