Emerging roles for vascular smooth muscle cell exosomes in calcification and coagulation

Abstract

Vascular smooth muscle cell (VSMC) phenotypic conversion from a contractile to 'synthetic' state contributes to vascular pathologies including restenosis, atherosclerosis and vascular calcification. We have recently found that the secretion of exosomes is a feature of 'synthetic' VSMCs and that exosomes are novel players in vascular repair processes as well as pathological vascular thrombosis and calcification. Pro-inflammatory cytokines and growth factors as well as mineral imbalance stimulate exosome secretion by VSMCs, most likely by the activation of sphingomyelin phosphodiesterase 3 (SMPD3) and cytoskeletal remodelling. Calcium stress induces dramatic changes in VSMC exosome composition and accumulation of phosphatidylserine (PS), annexin A6 and matrix metalloproteinase-2, which converts exosomes into a nidus for calcification. In addition, by presenting PS, VSMC exosomes can also provide the catalytic surface for the activation of coagulation factors. Recent data showing that VSMC exosomes are loaded with proteins and miRNA regulating cell adhesion and migration highlight VSMC exosomes as potentially important communication messengers in vascular repair. Thus, the identification of signalling pathways regulating VSMC exosome secretion, including activation of SMPD3 and cytoskeletal rearrangements, opens up novel avenues for a deeper understanding of vascular remodelling processes.

Figure 1. Functional roles for VSMC exosomes

A, cytokines and growth factors induce phenotypic conversion of VSMCs accompanied by cytoskeletal remodelling and SMPD3 activation. These changes enable budding of exosomes in MVBs and MVB trafficking and docking to the plasma membrane. Exosomes are released in the extracellular space upon the fusion of MVBs and the plasma membrane. B, exosome composition defines the role of exosomes in vascular repair. Extracellular matrix proteins, integrins and miRNA stimulate vascular repair by stimulating cell adhesion and migration. Externalized PS forms the nidus for calcification by forming a complex with annexin A6. Vascular calcification is also facilitated by matrix degradation catalysed by matrix metalloproteinase‐2 (MMP2). Exosomal PS can also bind coagulation factors and may stimulate vascular thrombosis activated by tissue factor expressed by VSMCs.