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Ludwig et al. Vessel Plus 2020;4:8 I http://dx.doi.org/10.20517/2574-1209.2019.37 Page 3 of 4

Figure 1. A schematic visualizing the reprogramming of endothelial cells by exosomes. A: exosomes carry a variety of pro-angiogenic
factors including the ectonucleotidases CD39 and CD73. Besides surface-bound molecules, exosomes encapsulate pro-angiogenic
factors, nucleic acids, adenosine, and cAMP, as well as other purine metabolites; B: tumor-derived exosomes interact directly with
endothelial cells or reprogram other cells in the tumor microenvironment to release pro-angiogenic factors. All these interactions involve
signaling via adenosine receptors expressed on responder cells: specifically, A 2B R on endothelial cells, A 1 R on monocytes, A 2A R and A 2B R
on macrophages, and A 2B R and A 3 R on mast cells. miRNA: microRNA; VEGF: vascular endothelial growth factor; FGF: fibroblast growth
factor; TGF-b: transforming growth factor beta; MMPs: matrix metalloproteinases; ICAM-1: intercellular adhesion molecule 1; uPA:
urokinase-type plasminogen activator; IL-8: interleukin 8; cAMP: cyclic adenosine monophosphate

ADENOSINE-MEDIATED STIMULATION OF ANGIOGENESIS BY EXOSOMES
Taken together, the above findings suggest the presence of a possible link between angiogenesis and
exosome-associated adenosine, as presented in Figure 1. Specifically, it was shown that exosomes contribute
[18]
to extracellular adenosine production and hence might modulate ECs indirectly . Exosomes from diverse
cancer cell types exhibit potent ATP- and 5’-AMP-phosphohydrolytic activity, partly attributed to activity
[19]
of CD39 and CD73, respectively, on the surface of exosomes . This exosome-generated adenosine is
functionally active and can trigger a cyclic adenosine monophosphate (cAMP) response in A R-positive
2A
[19]
but not A R-negative cells .
2A
While it is well recognized that exosomes encapsulate functional proteins and nucleic acids, it is currently
unclear whether purine metabolites are encapsulated within exosomes. Sayner et al. recently reported
[20]
that EVs encapsulate cAMP to provide an additional second messenger compartment. Our preliminary data
show that exosomes not only encapsulate cAMP but also adenosine and adenosine metabolites (inosine,
hypoxanthine, and xanthine). This may indicate that exosomes can induce ADOR signaling independently
of the production of adenosine by exosome-associated enzymes. Adenosine in the lumen of exosomes is
protected against uptake and metabolism by other cells, such as red blood cells. Thus, exosomal adenosine
may represent a mechanism for adenosine to serve as a circulating, rather than strictly local, factor.

Exosome-associated adenosine emerges as a potential stimulator of angiogenesis in different settings.
Studying this pathway promises to uncover important aspects of exosome functions, which are ultimately
leading to the stimulation of blood vessel formation. Understanding this pathway might also help to find
targets for the stimulation or inhibition of exosome-induced angiogenesis.

DECLARATIONS
Authors’ contributions
Writing of the manuscript: Ludwig N
Supervision and editing of the manuscript: Jackson EK, Whiteside TL

Availability of data and materials
Not applicable.