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.

Abnormal Lysosomal Positioning and Small Extracellular Vesicle Secretion in Arterial Stiffening and Calcification of Mice Lacking Mucolipin 1 Gene

“…Next, we investigated whether exosome/sEV secretion triggers VC. Several studies revealed that both intimal and medial VC follow a common mechanistic pathway, namely increased extracellular vesicle secretion, especially exosomes (40-140 nm in size) in interstitial space [11,60]. Using fetuin-A labelling, Kapustin et al revealed the origin of calcifying exosomes in VSMC [8].…”

“…It is reported that the exosome secretion pathway is activated during VC, and modulations on such a pathway may be applied as novel approaches for VC prevention [8]. During VC progression, the phenotypic transition process involves cytoskeleton remodeling, such as intracellular modifications, which enhanced exosome secretion [11,12].…”

Arterial Calcification in Diabetes Mellitus

“…This is highly relevant to the human setting; London and colleagues demonstrated that low turnover bone disease arising from either parathyroid hormone (PTH) resistance or deficiency correlates with vascular calcium load 116 and arterial stiffness or PAD 117 in CKD-MBD. Serum phosphate levels at any level of renal function convey cardiovascular risk, and exert pro-inflammatory actions upon VSM that promote vesicle-mediated vascular mineralization 118, 119 . It has been proposed that the skeleton represent an important “buffer” for phosphate in CKD 120 , and that orthotopic osteoblast –mediated calcium phosphate (as hydroxyapatite) deposition in bone may be responsible for the vascular benefits of normal bone formation.…”

Correlation of computed tomography with carotid plaque transcriptomes associates calcification with lesion-stabilization

“…In atherogenesis, contractile SMCs modulate into a proliferative and synthetic phenotype that migrates from the media into the intima, secrete extracellular matrix (ECM) components and build the fibrous cap [5]. Within lesion, SMCs have been assigned broad phenotypic plasticity [5][6][7] and reported to coexist in various intermediate phenotypes. In a recent study, we have shown that SMCs in carotid atherosclerosis downregulate classical and hitherto unknown markers for cytoskeletal integrity as well as calcium (Ca) signaling (i.e.…”