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Page 6 of 10 Reiss et al. Vessel Plus 2020;4:19 I http://dx.doi.org/10.20517/2574-1209.2020.04

endothelial interaction, but it is known that pericytes can affect the endothelium through exosomes and so,
adipocyte-to-pericyte communication via exosomes may merit investigation [100] .

Both proteins and miRNAs within exosomes may be involved in their effects. Adipocyte exosomal miRNAs
can influence macrophages resident within adipose tissue towards an inflammatory direction and can be
delivered to the vasculature where in vitro studies have shown that they induce pro-atherogenic changes in
macrophages [101,102] . One example is miR-34a, which is expressed at a higher level in adipose tissue of obese
compared to lean mice and also, in obese compared to lean humans [101] . In mice, miR-34a downregulated
Kruppel like factor 4, a transcription factor that drives M2 macrophage polarization, and this resulted in
less M2 and more M1 macrophages in adipose tissue. In human studies, the number of circulating adipocyte-
derived extracellular vesicles has been found to correlate with insulin resistance in obese subjects and with
serum triglyceride levels [103,104] .

CONCLUSION
The link from obesity to adipose tissue dysfunction to adipose-derived exosome influence on
atherosclerosis is only being explored now. Many of the experiments cited in this review utilize particles
produced in vitro and then introduced into in vivo animal models. Even though this is a useful initial
approach towards understanding the effects of different particles, it does not provide cause-and-effect
evidence of what is occurring in humans in vivo. Rather, it guides direction for future studies.

Exosomes from adipose tissue are formed by inward budding of the limiting membrane of late endosomes,
fuse with the plasma membrane and released into the blood or extracellular fluid [105] . We now have the
technology to isolate exosomes of adipocyte origin directly from the blood for analysis of their content and
sequencing of their miRNAs [105] . As more miRNA sequences are found to affect specific signaling pathways,
we can expect further elucidation of how they impact multiple aspects of atheroma formation and
maturation. A working hypothesis is that obesity induces chronic low-grade inflammation within adipose
tissue leading to specific changes in exosome cargo from both adipocytes and resident macrophages. The
miRNA and protein in these exosomes enter the circulation, reach the blood vessels and influence the
endothelial monolayer, macrophages and the stability of the plaque. The adipocyte exosomes may also
indirectly foster atherosclerosis by playing a role in insulin resistance and type 2 diabetes. Exosomes from
adipose stem cells may exert protective, anti-inflammatory effects on macrophages, suggesting a means
to develop countermeasures to the pro-inflammatory influence of adipose tissue [106] . While it is clear that
macrophages are integral to the atherosclerotic process, their precise role is still uncertain. Macrophages
may be part of the formation of a plaque, or they may be attracted to lipid deposits within the arterial
wall and act as phagocytes absorbing these lipids, as has been observed in early atherosclerotic changes,
and may participate either way [107] . Whatever the context, the effect of exosomes on macrophages in
atherosclerosis is worthy of further study. Knowledge of processes through which adipose tissue exosomes
may accelerate atherosclerosis progression would open up an opportunity to mitigate these negative effects,
even in persons who do not lose weight. One such approach would be to design and produce exosomes
harboring antagomirs to neutralize undesirable and overexpressed miRNAs [108] .

DECLARATIONS
Acknowledgments
This work was supported by the Elizabeth Daniell Research Fund. We thank Robert Buescher for his
generous support.

Authors’ contributions
Researched data for the article, discussed its content, and wrote, reviewed, and edited the manuscript: Reiss
AB, Kasselman LJ, De Leon J