Cell Signaling via Exosomes in the Development of Vascular Calcification
Vascular calcification is a feature of aging, a process in which cells in the blood vessel wall take on inappropriate identities and activities that are more appropriate to bone tissue. Evidence of recent years implicates chronic inflammation and the presence of senescent cells in this process. Senescent cells cause harm via their signaling, a good fraction of which is carried via forms of extracellular vesicle, such as exosomes. Here, researchers review what is known of the signaling that may be involved in changing the behavior of cells towards calcification processes. Whether or not it is necessary to understand all of this in order to find a way to block calcification is an interesting question: how much benefit will be produced by reducing inflammation and clearing senescent cells? If a sizable fraction of the problem remains, then a greater understanding will likely be required for further progress.
Vascular calcification (VC) is the abnormal deposition of calcium, phosphorus, and other minerals in the vessel wall in the form of hydroxyapatite. Over 60% of elderly people have calcium salt deposits in the vascular walls, and VC is closely associated with mortality from cardiovascular diseases in the aged population. Traditionally, calcification is considered as a degenerative disease associated with the aging process. However, increasing evidence has demonstrated that the occurrence and development of calcification is an active and highly regulated complex biological process, which is regulated by multiple factors, such as phenotypic conversion of vascular smooth muscle cells (VSMCs), metabolic homeostasis of calcium and phosphate, inflammation, oxidative stress, autophagy, and extracellular vesicle (EVs) release, among others.
Exosomes, as important intercellular message transporters, have recently been shown to participate in VC. Exosomes cargos include RNA, cytokines, proteins, and lipids. Studies have shown that the components of exosomes cargos differ significantly according to the cells that the exosomes origin. A large number of studies have focused on the role of exosomes in inducing mineral deposition during VC, but the role of exosomes in information transfer in VC has not yet been clarified.
Exosomes from different sources can participate in the regulation of VC by transporting miRNAs to recipient VSMCs. Exosomes released by mineralized osteoblasts contribute to the osteogenic differentiation of cells via a complex network of exosomal miRNAs. Bone marrow mesenchymal stem cell (MSC)-derived exosomes can alleviate high phosphorus-induced calcification in human aortic VSMCs through the modification of miRNA profiles. Exosomes derived from VSMCs are rich in miRNA-143 and proteins regulating cell adhesion and migration, which can participate in the regulation of cell proliferation and migration through autocrine and paracrine manners. An in vivo study showed that exosomes derived from melatonin-treated VSMCs could reduce VC in mice, while these effects were largely abolished by inhibition of exosomal miR-204 or miR-211.
The underlying mechanisms by which exosomes affect VC via transporting miRNA are still not fully understood and may vary among different conditions. Changes of miRNAs in exosomes can regulate osteogenic differentiation of cells by promoting the expression of Runx2 and activating related signaling pathways, for example, the Wnt/β-catenin pathways. Studies have shown that miRNAs with increased expression in the VC process can promote the osteogenic transformation of smooth muscle cells by targeting anti-calcification proteins or contractility markers, while miRNAs with decreased expression can inhibit the osteogenic transformation of SMCs by targeting osteogenic transcription factors. Further research on the characteristics of exosomes and their role in VC is needed and expected to provide novel ideas and targets for the clinical diagnosis and treatment of VC.