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Page 2 of 4 Ludwig et al. Vessel Plus 2020;4:8 I http://dx.doi.org/10.20517/2574-1209.2019.37

ROLES OF EXOSOMES IN ANGIOGENESIS
[2]
One hallmark of exosomes is the promotion of angiogenesis. Skog et al. reported in 2008 that
glioblastoma-derived exosomes contain mRNA, microRNA (miRNA), and angiogenic proteins and that
these exosomes reprogram endothelial cells (ECs) to an angiogenic phenotype. A variety of research groups
[2]
extended the work of Skog et al. addressing the pro-angiogenic functions of exosomes in different health
and disease settings. Multiple pathways which are used by exosomes to stimulate blood vessel formation
[3]
were uncovered in recent years and most research focuses on the direct interaction of exosomes with ECs .
It was shown that exosomes can deliver signals to receptors on ECs, which activate the relevant molecular
[3]
pathways and contribute to altered cellular responses . The reported ligands on the surface of exosomes
which can induce an angiogenic response include vascular endothelial growth factor (VEGF), interleukin
6 (IL-6), IL-8, fibroblast growth factors (FGF), and urokinase-type plasminogen activator (uPA) [2,4] .
[4]
Besides surface-mediated receptor-ligand interactions, ECs internalize exosomes within 2-4 h . Numerous
pathways are utilized by ECs for the internalization of exosomes, such as phagocytosis, micropinocytosis,
[5]
or lipid raft-mediated internalization . However, the main uptake mechanism is endocytosis, as recently
[4]
reported . The internalization of exosomes allows for the delivery of messages that are then translated
[2]
by ECs . miRNAs are frequently described components of the exosome cargo which can induce pro-
[6]
angiogenic responses in ECs .
ADENOSINE PATHWAY AND ANGIOGENESIS
In addition to these well-described pathways, signaling via purines may also contribute to exosome-mediated
effects on angiogenesis. One pathway that has not been studied thus far and that is particularly interesting
in the context of exosomes and angiogenesis is the adenosine pathway. Extracellular adenosine exhibits a
broad range of effects on cell cycle control, immunoregulation, and cytokine regulation through both direct
[7]
and indirect mechanisms and ultimately leads to the progression of malignant diseases . Additionally,
adenosine has been recognized as a potent stimulator of angiogenesis and Adair estimated that adenosine
[8,9]
[10]
can contribute up to 50%-70% of the angiogenic response in some situations . Adair et al. also described
that intravenous infusion of adenosine can increase plasma levels of VEGF in humans. In cultured cells,
it was shown that adenosine induces EC proliferation and migration by increasing levels of VEGF and
[9]
other angiogenic growth factors . Additionally, adenosine can stimulate EC proliferation independently of
VEGF, which probably involves modulation of other pro-angiogenic and anti-angiogenic growth factors and
[9]
perhaps an intracellular mechanism .
Initiation of the adenosine signaling cascade requires binding of adenosine to the specific adenosine receptors
(ADORs), which are divided into four subtypes: A R, A R, A R and A R. The main difference between
3
1
2B
2A
these receptors is the affinity for adenosine, since adenosine binds to A R, A R and A R in the nanomolar
3
1
2A
[11]
range, whereas adenosine binds to A R in the micromolar range . This indicates that physiologic
2B
concentrations are sufficient to induce A R-, A R- and A R-mediated signaling, and elevated adenosine
2A
1
3
concentrations, which are usually found in inflammatory or tumor microenvironments, can activate an A R-
2B
[11]
signaling cascade . It was shown that adenosine induces EC growth by activating A R and that A R plays
2B
2B
a critical role in regulating vascular remodeling associated with EC proliferation in angiogenesis, collateral
vessel development, and recovery after vascular injury [12,13] . However, the other receptor subtypes have
also been reported to be involved in angiogenesis. Although there is no direct stimulation of ECs, ADORs
act in a functional cooperative fashion to promote angiogenesis by a paracrine mechanism involving the
[16]
differential expression and secretion of angiogenic factors from other cell types [14,15] . Ernens et al. reported
that adenosine upregulates thrombospondin-1 production by macrophages via A R and A R, resulting in
2B
2A
stimulation of angiogenesis. Adenosine also stimulates the production of VEGF, IL-8, and angiopoetin-1
[17]
[15]
from mast cells via A R and A R, as reported by Feoktistov et al. . Clark et al. demonstrated that A R
3
1
2B
activation elicits an angiogenic response and promotes VEGF-release from cultured monocytes. Thus,
the literature suggests that all ADORs are involved in regulating blood vessel development, and that the
underlying pathway for stimulating angiogenesis is highly context/microenvironment-dependent.