Extracellular vesicles in atherosclerosis and vascular calcification: the versatile non-coding RNAs from endothelial cells and vascular smooth muscle cells

Abstract

Atherosclerosis (AS) is characterized by the accumulation of lipids, fibrous elements, and calcification in the innermost layers of arteries. Vascular calcification (VC), the deposition of calcium and phosphate within the arterial wall, is an important characteristic of AS natural history. However, medial arterial calcification (MAC) differs from intimal calcification and cannot simply be explained as the consequence of AS. Endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are directly involved in AS and VC processes. Understanding the communication between ECs and VSMCs is critical in revealing mechanisms underlying AS and VC. Extracellular vesicles (EVs) are found as intercellular messengers in kinds of physiological processes and pathological progression. Non-coding RNAs (ncRNAs) encapsulated in EVs are involved in AS and VC, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). The effects of ncRNAs have not been comprehensively understood, especially encapsulated in EVs. Some ncRNAs have demonstrated significant roles in AS and VC, but it remains unclear the functions of the majority ncRNAs detected in EVs. In this review, we summarize ncRNAs encapsulated in EC-EVs and VSMC-EVs, and the signaling pathways that are involved in AS and VC.

Keywords: atherosclerosis (AS); extracellular vesicles (EVs); non-coding RNAs (ncRNAs); uremia; vascular calcification (VC).

Figure 1

EVs in the microenvironment of IAC in AS and MAC. (A) Three layers of arteries: tunica externa, tunica media (mainly composed of VSMCs), and tunica intima (composed of ECs and subendothelial layer). VSMCs and ECs are both the donor cells and recipient cells in the microenvironment of vascular. Circulating EVs in serum and EVs derived from VSMCs and ECs have been involved in cellular communication. (B) Platelet, monocyte, macrophage, neutrophil, transitional VSMCs, and dysfunctional ECs are involved in AS and IAC. EVs derived from VSMCs and ECs are novel messengers in the microenvironment of AS. (C) Dysfunctional ECs and transitional VSMCs are involved in MAC. EVs derived from VSMCs and ECs are novel messengers in the microenvironment of MAC. EVs, extracellular vesicles; IAC, intimal arterial calcification; AS, atherosclerosis; MAC, medial arterial calcification; VSMCs, vascular smooth muscle cells; ECs, endothelial cells. Created with BioRender.com.

Figure 2

ncRNAs encapsulated in EC-EVs and VSMC-EVs regulate the AS process. Various stimuli stimulate the release of EVs and ncRNAs encapsulated in EC-EVs, and VSMC-EVs are assimilated by different recipient cells, resulting in AS inhibition or promotion. ncRNAs (miR-155-5p, miR-505-3p, miR-19b-3p, miR-4306, miR-92a-3p, MALAT1, ZEB1-AS1, CLDN10-AS1, LINC01005, and hsa_circ_0086296) encapsulated in EVs derived from ECs induced by different stimuli (LPS, extra-virgin-olive, ox-LDL, IL-6, TNF-α, shear flows, and chrysin) were linked to AS via enhancing ECs and VSMCs phenotype switching, promoting M1 macrophages activation, M2 macrophage polarization, NETs formation, lipid formation of macrophages, and endothelial injuries; miR-143-3p and miR-145-5p encapsulated in EVs derived from ECs stimulated by KLF2-transduced and shear-stress induced an atheroprotective VSMC phenotype; ncRNAs (miR-143-3p, miR-222-3p, miR-155-5p, and hsa_circ_0001445) encapsulated in EVs derived from VSMCs induced by stimuli (including hypercholesterolemia, KLF5, and ox-LD) were linked to AS by reducing expressions and enhancing endothelial injuries. ncRNAs, non-coding RNAs; VSMCs, vascular smooth muscle cells; ECs, endothelial cells; EVs, extracellular vesicles; AS, atherosclerosis; LPS, lipopolysaccharide; ox-LDL, oxidized low-density lipoprotein; IL-6, interleukin-6; TNF-α, tumor necrosis factor-a; NETs, neutrophil extracellular traps; KLF2, Krüppel-like factor 2; KLF5, Krüppel-like factor 5. Created with BioRender.com.

Figure 3

ncRNAs encapsulated in EC-EVs and VSMC-EVs regulate the VC process. Various stimuli stimulate the release of EVs and ncRNAs encapsulated in EC-EVs, and VSMC-EVs are assimilated by VSMCs, resulting in VC inhibition or promotion. miR-670-3p, miR-221-3p, and miR-222-3p encapsulated in EVs derived from ECs induced by stimuli (HP, uremic toxins, transverse aortic constriction, and advanced glycation end-products) promoted VC, while miR-143-3p, miR-145-5p, miR-29b-3p, and miR-126-5p inhibited VC; miR-92b-3p, miR-204-5p, and miR-211-5p encapsulated in EVs derived from VSMCs induced by stimuli (curcumin and melatonin), inhibited VC; the profiles of miRNAs encapsulated in EVs derived from VSMCs (β-GP and pyruvic acid-induced MOVAS-1 and cystic kidney disease rats VSMCs) have been detected. ncRNAs, non-coding RNAs; EVs, extracellular vesicles; VSMCs, vascular smooth muscle cells; ECs, endothelial cells; VC, vascular calcification; HP, high phosphate; β-GP, β-glycerophosphate. Created with BioRender.com.