ATVB in Focus

The Role of Adenosine in Response to Vascular Inflammation

Series Editor: Joel Linden

Adenosine Signaling
Good or Bad in Erectile Function?
Jiaming Wen, Yang Xia
Abstract The erectile status of penile tissue is governed largely by the tone of cavernosal smooth muscle cells, which is
determined by the balance of vascular relaxants and constrictors. Vascular relaxants play a key role in regulating the tone of
cavernosal smooth muscle and thus the initiation and maintenance of penile erection. Early studies drew attention to the
potential role of adenosine signaling in this process. However, the serendipitous discovery of the effect of sildenafil on erectile
physiology drew more attention toward nitric oxide (NO) as a vasodilator in the process of penile erection, and a recently
discovered, unexpected erectile phenotype of adenosine deaminase deficient mice reemphasizes the importance of adenosine
as a key regulatory of erectile status. Adenosine, like NO, is a potent and short-lived vasorelaxant that functions via cyclic
nucleotide second messenger signaling to promote smooth muscle relaxation. Recent studies reviewed here show that
adenosine functions to relax the corpus cavernosum and promote penile erection. Excess adenosine in penile tissue contributes
to the disorder called priapism, and impaired adenosine signaling is associated with erectile dysfunction. More recent research
summarized in this review reveals that adenosine functions as a key endogenous vasodilator in the initiation and maintenance
of normal penile erection. This new insight highlights adenosine signaling pathways operating in penile tissue as significant
therapeutic targets for the treatment of erectile disorders. (Arterioscler Thromb Vasc Biol. 2012;32:845-850.)
Key Words: adenosine signaling erectile dysfunction penile erection priapism

enile erection is a neurovascular event modulated by

psychological factors and hormonal status. The erectile
status of penile tissue is governed largely by the tone of
cavernosal smooth muscle cells, which is determined by the
balance of vascular relaxants and constrictors.1 The flaccid
state is maintained by chronic release of noradrenaline from
cavernosal nerves that keep the cavernosal smooth muscle
cells contracted, collapsing the sinusoidal spaces and preventing blood flow into the tissue. On sexual stimulation, the
release of specific neurotransmitters from the cavernous
nerves and of relaxing factors from the endothelial cells leads
to cavernosal smooth muscle relaxation and the flow of blood
into the sinusoidal spaces, which become expanded. This
results in an increase in intracavernosal pressure and compression of subtunical veins against the tunica albuginea,
thereby restricting outflow of blood from corpus cavernosum
with consequent tissue engorgement.2,3 Thus, penile erection
is largely a hemodynamic process based on regulated entry of
blood into the sinusoidal spaces of the corpus cavernosum.

Introduction to Adenosine Signaling

Adenosine is a pleiotrophic signaling nucleoside that
elicits a multitude of effects on target cells by engaging

specific G protein coupled receptors.4 Four such receptors

have been described, ADORA1, ADORA2A, ADORA2B,
and ADORA3. Each receptor has a unique affinity for
adenosine and a distinct cellular and tissue distribution. In
most cases, ADORA1 and ADORA3 are coupled to adenylyl
cyclase by the inhibitory G protein subunit (Gi) and hence
serve to lower intracellular levels of the second messenger
cAMP.58 ADORA2A and ADORA2B are commonly coupled to adenylyl cyclase by the stimulatory G protein subunit
(Gs) and serve to increase intracellular cAMP8,9 (Figure 1).
Adenosine is generated intracellularly and extracellularly by
degradation of adenine nucleotides. Under normal physiological
conditions, intra- and extracellular levels of adenosine are in the
nanomolar range, but they rise into millimolar concentrations
under stressful conditions such as hypoxia, ischemia, and cellular damage.1013 Intracellularly, adenosine is formed predominantly by dephosphorylation of adenosine monophosphate
(AMP), catalyzed by intracellular cytosolic enzyme 5=nucleotidase. Hydrolysis of S-adenosyl-homocysteine also contributes to intracellular adenosine formation.4 Inside the cell,
adenosine is further metabolized by 2 enzymes, adenosine
kinase (ADK) and adenosine deaminase (ADA). ADK phosphorylates adenosine to AMP, whereas ADA catalyzes the

Received on: December 8, 2011; final version accepted on: January 18, 2012.
From the Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, TX (J.W., Y.X.); Department of Urology;
Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China (J.W.).
Correspondence to Yang Xia, Department of Biochemistry and Molecular Biology, UT Houston Medical School, PO Box 20708, Houston, Texas
77225. E-mail yang.xia@uth.tmc.edu
2012 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org

DOI: 10.1161/ATVBAHA.111.226803

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Figure 1. Adenosine is generated intracellularly and extracellularly

by degradation of adenine nucleotides. Intracellularly, adenosine is
formed predominantly by dephosphorylation of adenosine monophosphate (AMP), catalyzed by intracellular cytosolic enzyme
5=-nucleotidase. Hydrolysis of S-adenosyl-homocysteine (AdoHcy)
by S-adenosyl-homocysteine hydrolase (SAHH) also contributes to
intracellular adenosine formation. Inside the cell, adenosine is further metabolized by 2 enzymes, adenosine kinase (ADK) and adenosine deaminase (ADA). ADK phosphorylates adenosine to AMP,
whereas ADA catalyzes the irreversible deamination of adenosine to
inosine. Adenosine is also generated extracellularly by degradation of
adenine nucleotides. ATP is released from neurons as neurotransmitters and when the cell membrane is subjected to mechanical stress.
Extracellular adenine nucleotides are initially dephosphorylated by the
ectonucleotidase CD39, which hydrolyzes ATP to ADP and ADP to
AMP. Ecto-5=-nucleotidase (CD73) catalyzes the dephosphorylation of
AMP to adenosine and is generally the rate-limiting step in the formation of adenosine from extracellular adenine nucleotides. Adenosine is
a pleiotrophic signaling nucleoside that elicits a multitude of effects on
target cells by engaging specific G proteincoupled receptors. Four
such receptors have been described: ADORA1, ADORA2A,
ADORA2B, and ADORA3.

irreversible deamination of adenosine to inosine. Adenosine is

also generated extracellularly by degradation of adenine nucleotides. ATP is released from neurons as a neurotransmitter and
when the cell membrane is subjected to mechanical stress.14
Extracellular adenine nucleotides are initially dephosphorylated
by the ectonucleotidase CD39, which hydrolyzes ATP to ADP
and ADP to AMP. Ecto-5=-nucleotidase (CD73) catalyzes the
dephosphorylation of AMP to adenosine15 and is generally the
rate-limiting step in the formation of adenosine from extracellular adenine nucleotides (Figure 1).

Adenosine Signaling and Penile Erection

Exogenous Adenosine Induces Cavernosal Smooth
Muscle Relaxation
Adenosine, like nitric oxide (NO), is a potent vasodilator and
has long been implicated in the regulation of penile erection.2,1619 Early studies in dogs showed that intracavernous
injection of adenosine induced a full erection, which was
independent of acetylcholine.20 Takahashi et al21 further investigated the hemodynamic effects of intracavernous injection of adenosine in dogs. They found that adenosine increased arterial blood flow and intracavernous pressure,
thereby inducing penile erection in a dose-dependent manner.21 Adenosine-mediated increased intracavernous pressure
was potentiated by pretreatment with an equilibrative nucleoside transporter inhibitor and was significantly decreased by

the nonselective adenosine receptor antagonist theophylline.21 These studies indicate that adenosine is capable of
inducing penile erection via adenosine receptor signaling. Wu
et al22 reported that adenosine induced relaxation of the
corpus cavernosum of rabbits, under both baseline tension
and precontraction. More importantly, Chiang et al23 observed dose-dependent inhibition of nerve stimulated contraction of corpus cavernosal strips (CCSs) of rabbits by adenosine and its analogs (5=-N-ethyl-carboxamidoadenosine or
R-phenylisopropyl adenosine). Filippi et al24 observed that
adenosine relaxed the precontracted human corpus cavernous
strips in a dose-dependent manner and at high concentrations
almost completely relaxed the tissue. Similarly, adenosine and
its analogs induce relaxation in corpus cavernous strips from
mice.2428 Taken together, both in vitro and in vivo studies
demonstrate that adenosine is capable of inducing corpus cavernosal relaxation and penile erection in multiple species.

The Importance of Adenosine Receptor Signaling

To identify which adenosine receptor mediated cavernosal
smooth muscle relaxation, Mi et al measured CCS relaxation in
each of the 4 adenosine receptor deficient mice in response to
different dosages of adenosine.27 The results show that
Adora1/, Adora2a/, Adora3/, and wild-type mice displayed a dose-dependent increase in relaxation in response to
increasing concentrations of adenosine. In contrast, the
adenosine-dependent relaxation was completely absent in CCSs
from Adora2b/ mice. In earlier work, Chiang et al23 provided
pharmacological evidence that the ADORA2B contributed to
cavernosal smooth muscle relaxation in the rabbit. Overall, these
results provide strong evidence that the ADORA2B receptor is
required for CCS relaxation in response to adenosine.

Downstream Signaling in Cavernosal Smooth

Muscle Cells
To determine the signaling components functioning downstream of ADORA2B, Mi et al measured cAMP levels in
response to adenosine in the cultured isolated CCSs of both
wild-type and ADORA2B receptor-deficient mice. The results showed that adenosine induced cAMP levels in a
dose-dependent manner in wild-type cells but not in Adora2b
receptor-deficient CCSs. Similarly, they found that the
adenosine-mediated induction of cAMP in wild-type CCSs
was inhibited by an ADORA2B antagonist. Thus, both
genetic and pharmacological evidence indicates that adenosine acts via ADORA2B signaling to induce cAMP levels in
CCSs to induce relaxation.27
To determine the cell types involved with ADORA2B
signaling in the penis, Mi et al purified and cultured corpus
cavernosal smooth muscle cells (CCSMCs) from wild-type
and Adora2b-deficient mice.27 Analysis of CCSMC RNA
from wild-type mice showed that Adora2b RNA was the most
abundant adenosine receptor RNA in these cells. Additional
experiments showed that adenosine mediated induction of
cAMP in CCSMCs was blocked by an ADORA2B antagonist
and was absent in CCSMCs of Adora2b-deficient mice. Overall,
these results provide additional pharmacological and genetic
evidence that ADORA2B signaling is required for adenosinemediated stimulation of cAMP production in CCSMCs.27

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Increased Endogenous Adenosine Production in

Penile Tissues in Response to Cavernosal
Nerve Stimulation
The experiments described above involved either the injection of
adenosine into penile tissue or the addition of adenosine to tissue
explants or primary cell cultures. In each of these cases,
adenosine (or adenosine analogs such as 5=-N-ethylcarboxamidoadenosine) are added exogenously. In an effort to
determine whether the regulated production of endogenous
adenosine plays a direct role in penile erection, Wen et al29,30
used a well-established method to mimic normal physiological
erection by electric stimulation of the cavernous nerve to induce
an erectile response.3133 Flacid penile tissue was obtained as a
control from sham-operated unstimulated mice. Tissue extracts
from flaccid and erected penile tissue were fractionated by
high-pressure liquid chromatography to measure endogenous
adenosine levels. The results show that the concentration of
adenosine in penile tissue doubled as a result of cavernous nerve
stimulation. The functional importance of the adenosine produced as a result of cavernosal nerve stimulation is illustrated by
experiments described in the following paragraph.

The Role of Ectonucleotidases in Extracellular

Adenosine Production
The activation of certain presynaptic neurons results in the
release of ATP can be converted to extracellular adenosine by
the sequential action of ectonucleotidases. In many circumstances, a cell-surface ecto-5=-nucleotidase termed CD73
catalyzes the rate-limiting step in the conversion of extracellular adenine nucleotides to adenosine (Figure 1). Histological analysis revealed that this enzyme is widely expressed in
penile tissue, with remarkably high levels in the nerve
bundles, smooth muscle, and endothelium. To assess the
functional role of CD73 in adenosine production, Wen et
al29,30 measured adenosine levels in penile tissue in wild-type
and CD73-deficient mice with or without cavernous nerve
stimulation. The results showed that adenosine levels in penile
tissue of CD73-deficient mice were significantly lower than that
of wild-type mice and that no increase in adenosine levels
resulted from cavernous nerve stimulation of CD73-deficient
mice. These findings show that CD73 is essential for adenosine
production within penile tissues in response to cavernous nerve
stimulation in vivo. Additional genetic and pharmacological
studies showed that CD73-mediated adenosine production contributes to the initiation and maintenance of penile erection
following cavernous nerve stimulation. Overall, these results
indicate that endogenous adenosine induced by nerve stimulation plays important role in normal penile erection.

Sheer StressMediated Production of Adenosine

Subsequent to the initiation of penile erection, blood flowmediated sheer stress of endothelial cells contributes to the
maintenance of penile erection by the activation of phosphatidylinositol 3-kinaseAKT signaling and the activation of
endothelial nitric oxide synthase (eNOS). One molecule
known to be released by shear stress from endothelial cells is
ATP, which is quickly converted to adenosine. A role for
adenosine as the mediator linking shear stress with eNOS
activation was revealed by studies of Wen et al,29,30 who showed

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847

that increased ATP release and elevated CD73 expression

contributed to increased extracellular adenosine production by
shear-stressed endothelial cells. Additional studies showed that
shear stress-mediated elevated adenosine functions through the
ADORA2B to activate the phosphatidylinositol 3-kinaseAKT
signaling cascade, resulting in increased eNOS phosphorylation
and NO production. Subsequent in vivo studies showed that
adenosine is induced during sustained penile erection and
contributes to phosphatidylinositol 3-kinaseAKT activation and
subsequent eNOS phosphorylation via ADORA2B signaling.
Overall, these findings identified a previously unrecognized role
of adenosine signaling in penile erection and revealed the
underlying mechanisms accounting for adenosine production
and signaling pathways involved in the process. These findings
also reveal novel therapeutic possibilities for the treatment of
disorders of erectile function.

Priapism: A Condition Resulting From

Excessive Adenosine Signaling
Priapism is a condition of persistent penile erection lasting more
than 4 hours in the absence of sexual excitation. Although
uncommon in the general population, it was recognized as a
serious complication of sickle cell disease (SCD) as early as
1934.34 Priapism is a dangerous and urgent condition because of
its major complication, penile fibrosis. Because priapism is
poorly understood, there are no mechanism-specific treatment
options for the disorder except evacuation of blood and draining
of the corpus cavernosum to relieve engorgement, coupled with
intracavernosal injection of an -adrenergic receptor agonists to
stimulate cavernosal smooth muscle contraction. Some researchers used red blood cell exchange pheresis to treat priapism
associated with SCD. However, no randomized clinical trials
have been performed to determine its clinical efficacy.35

An Unexpected Phenotype of Adenosine

DeaminaseDeficient Mice
Priapism is known to be associated with hypoxic and ischemic
conditions. Although adenosine is known to be induced under
hypoxic and ischemic conditions,13,36 the pathological role of
adenosine in priapism was not recognized until an unexpected
priapism phenotype in adenosine deaminase (ADA) deficient
mice was observed.27 ADA is a purine metabolic enzyme that
catalyzes the conversion of adenosine to inosine. As a result of
ADA deficiency, these mice exhibit a marked increase in
adenosine concentrations, particularly in the penis, which has the
highest level of adenosine among all the tissues examined. These
mice display features of priapism seen in humans, including
spontaneous and prolonged penile erection, increased vascular
relaxation in response to neurostimulation, and penile fibrosis.
The spontaneously occurring priapism observed with ADAdeficient mice was quickly relieved by intraperitoneal injection
of polyethylene glycol modified (PEG)-ADA. This observation
provided the initial clue that elevated adenosine in the penes of
Ada/ mice was responsible for the spontaneous prolonged
penile erection. These findings indicate that ADA-deficient mice
represent a novel and important animal model to study the role
of adenosine signaling in priapism.

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Molecular Mechanisms of
Adenosine-Induced Priapism
ADA-deficient mice are a well-accepted animal model to
study the contribution of excessive adenosine signaling to
various pathological conditions. SCD transgenic (Tg) mice
are a well-accepted animal model of priapism. These 2 lines
of genetically modified mice were studied as mouse models
of priapism. To further evaluate the role of adenosine signaling in priapism, we tested the effect of PEG-ADA on electric
field stimulationinduced relaxation of CCS for both ADAdeficient mice and SCD mice. The results show that 60 seconds
of electric field stimulation at 5 V and 30 Hz evoked a
substantial and prolonged relaxation of CCS from ADAdeficient mice and SCD Tg mice in comparison with CCS from
control mice. Consistently, treatment of CCS in ADA-deficient
mice and SCD Tg mice with PEG-ADA inhibited the increased
CCS vascular relaxation. Thus, these results indicate that elevated adenosine contributes to the prolonged penile erection and
substantial penile vascular relaxation with ADA-deficient mice.
The analysis of 4 adenosine receptor deficient mice revealed
that the ADORA2B is essential for adenosine-dependent penile
vascular smooth muscle relaxation and erection and that upregulated ADORA2B signaling contributes to priapic activity in
ADA/ mice. Additional studies showed that priapic activity in
SCD Tg mice was also due to elevated adenosine signaling via
ADORA2B signaling, suggesting a general contributory role of
adenosine and ADORA2B signaling in priapism. This signaling
pathway represents a potentially important therapeutic target for
the treatment of priapism.

PEG-ADA May Be Useful in the Prevention and

Treatment of Priapism
To address the role of adenosine in priapism seen in ADAdeficient mice, we regulated adenosine levels in ADAdeficient mice with different amounts of PEG-ADA enzyme
therapy. The ADA-deficient mice were maintained on high
dose enzyme therapy at 5 U per week for at least 8 weeks to
allow for normal penile development. At 8 weeks of age, the
dose of PEG-ADA was gradually tapered down to a low dosage
at 0.625 U per week. After 2 weeks at the low dosage of
PEG-ADA treatment, we found that 25% mice displayed
spontaneously prolonged penile erection lasting for 12 to 72
hours. Strikingly, the prolonged penile erections observed in
these ADA-deficient mice were quickly corrected (around 6 7
minutes) by intraperitoneal injection of a high dose of PEGADA. This data indicated that PEG-ADA enzyme therapy
quickly corrects the priapism observed in ADA deficient mice.
To confirm this in vivo finding, we treated ADA-deficient
mice and SCD Tg mice with different dosage of PEG-ADA to
adjust adenosine to different levels in vivo. At the end of each
experiment, adenosine levels in penile tissue were determined
by high-pressure liquid chromatography. Erectile function
was determined by CCS relaxation in response to electric
field stimulation. The results showed a high dosage regimen
of PEG-ADA enzyme therapy from birth in ADA-deficient
mice prevented the increased electric field stimulationinduced CCS relaxation by lowering penile adenosine levels to
normal. The significance and general utility of PEG-ADA
enzyme therapy in priapism was confirmed and extended by

showing that PEG-ADA treatment normalized penile adenosine levels in SCD Tg mice and relieved the priapic features
in these.37 Taken together, our preclinical studies with 2
mouse models of priapism have identified a novel application
of PEG-ADA as a safe and mechanism-based drug in prevention and treatment of priapism. Additional therapeutic
approaches for the treatment of priapism may include the use
of ADORA2B antagonists. These findings provide a strong
justification for clinical trials in men experiencing priapism.
The Role of Adenosine Signaling in Penile Fibrosis
Associated With Priapism
Penile fibrosis is dangerous and urgent complication of
priapism because it eventually results in erectile dysfunction
(ED). The pathogenesis of penile fibrosis associated with
priapism likely results from a combination of prolonged
penile erection, ischemic-mediated inflammatory response,
vascular damage and attempted tissue repair.36 Multiple
factors are released from locally insulted penile tissue and
responding cells. Previous studies have demonstrated the role
of extracellular nucleotide release in acute inflammatory
conditions.38 In contrast, chronically persistently elevated
adenosine is known to induce fibrosis in the lung and
kidneys.39,40 Recently, Wen et al41 have demonstrated that
elevated adenosine levels in penile tissue contribute to vascular damage and penile fibrosis associated with priapism,
and further studies have shown that chronic reduction of
adenosine by PEG-ADA enzyme therapy prevented and
attenuated the progression of vascular damage and the increased profibrotic gene expression associated with penile
fibrosis in both ADA-deficient mice and SCD Tg mice. Mechanistically, using both pharmacological and genetic tools, we
determined that transforming growth factor- functions downstream of the ADORA2B and is responsible for excess
adenosine-mediated penile fibrosis seen in both lines of mice.
Overall, these preclinical studies have identified a previously
unrecognized novel application of PEG-ADA as a safe, effective, and mechanism-based drug to treat and prevent priapism
and penile fibrosis in animals and provide a strong justification
for clinical trials in men experiencing priapism.41

Adenosine Signaling in SCD and

Adenosine-Based Therapy
The functional role of adenosine signaling in SCD disease is
not limited to priapism. For example, earlier studies by
Wallace et al have demonstrated that activation of
ADORA2A is capable of inhibition of invariant natural killer
T cells in the lung and subsequent decreases pulmonary
dysfunction in the NY1DD mouse model of SCD.42 More
recently, our laboratory has demonstrated that elevated adenosine is detrimental to induce erythrocyte sickling, a central
pathogenesis of SCD, in both Berkley SCD mice and in
cultured human sickle erythrocytes. We further demonstrated
that excessive adenosine signaling through the ADORA2B
triggers sickling by induction of 2,3-diphosphoglycerate, an
erythroid specific metabolite that induces O2 release from
hemoglobin in both SCD mice and humans.43 These findings
show that adenosine has dual roles in the pathogenesis of
SCD by working on different adenosine receptors on different

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cell types: (1) ADORA2A activation on invariant natural
killer T cell leads to inhibition of lung dysfunction in SCD
mice; and (2) ADORA2B activation on erythrocytes induces
sickling by increasing 2,3-diphosphoglycerate production and
subsequently promoting deoxygenation and polymerization.
These findings pointed out novel adenosine-based therapeutic
implications for SCD.44 In view of the potentially beneficial
effects of adenosine-mediated ADORA2A activation on invariant natural killer T cells,42 an ADORA2B antagonist may
be a better choice than PEG-ADA because it will specifically
block only 1 of the 4 adenosine receptors without the loss of
potentially beneficial effects resulting from the activation of
other adenosine receptors on different cell types.

Defective Adenosine Signaling and ED

ED is characterized by the inability to develop or maintain an
erection sufficient to permit satisfactory sexual intercourse.2
Based on the causes, ED is classified into psychogenic and
organic. Causes of organic ED can be neurogenic, hormonal, or
vasculogenic in nature. Organic ED can also be a result of aging
or systemic disease, such as diabetes or chronic renal failure.2
The etiology of vasculogenic ED has been associated with
reduced NO formation either from nerve fibers or from
endothelial cells of the corpus cavernosum. Early work by
Chiang et al23 indicated that the relaxing effect of adenosine
in rabbit cavernosal tissue is partially endothelium dependent
and involves the release of endothelium-derived relaxing
factors, presumably NO. Pharmacological evidence provided
by Chiang et al23 indicated that the adenosine receptors
involved in this response were of the A2B subtype. More
recent data by Faria et al25 also showed that adenosineinduced relaxation of human CCS was stimulated by endothelium derived NO produced as a result of ADORA2B
activation. These findings are consistent with our data showing that in mice penile smooth muscle relaxation produced by
adenosine is mediated in large part by the synthesis and
release of NO following the activation of NO synthase
secondary to intracellular signaling cascades resulting from
ADORA2B activation, presumably on endothelial cells.
A potential role for impaired adenosine signaling in ED
was reported by Faria et al,25 who observed partial resistance
of corpus cavernosum from men with vasculogenic impotence to adenosine-induced relaxation and showed that dysfunctional ADORA2B, supposedly on the endothelium, are
the cause for the signaling impairment.
Adenosine, because of its vasorelaxant properties, has always
been looked on as a potential treatment for ED. Chiang et al23
evaluated the potential of adenosine as a treatment for ED. They
observed that intracorporeal injection of adenosine in impotent
men caused increased cavernosal arterial flow and resulted in
tumescence or suboptimal erection but failed to cause full
erection, whereas intracorporeal injection of prostaglandin E1
was able to induce full erection signaling via its receptor. PEG1
receptor activation leads to subsequent activation of adenyl
cyclase, induction of cAMP levels, and eventually relaxation of
vascular smooth muscle cells in corpus cavernosum. These
results are partly in agreement with those of Kilic et al,45 who
evaluated the potential of adenosine as an agent in the diagnosis
of vasculogenic impotence. Chiang et al23 attributed the lack of

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849

Figure 2. A model depicting regulation of adenosine production

and adenosine signaling during initiation and maintenance of penile
erection. ATP is known to be released from neuron via depolarization and endothelial cells via sheer stress, respectively, which is
strikingly similar to nitric oxide (NO) releasing from neuron and
endothelial cells in the penis during initiation and maintenance of
penile erection. Released ATP is rapidly dephosphorylated by
extracellular nucleotidases, such as CD73, to form extracellular
adenosine. Neuronal activationmediated ATP release leads to
increased adenosine, as neuronal nitric oxide synthases (nNOS)mediated NO release for initiation of penile relaxation and sheer
stressmediated ATP release results in increased adenosine for
maintenance of penile relaxation. Thus, the production of adenosine during penile erection leads to sustained and potent penile
erection via direct effect on vascular smooth muscle cells by induction of cAMP and indirect activation of endothelial nitric oxide synthase (eNOS) via phosphatidylinositol 3-kinaseAKT (PI3K-AKT)
adenosine in endothelial cells.

erection on adenosine injection to the rapid degradation of

adenosine, which was also the reason put forth by Kilic et al43
for the short duration of erection caused by adenosine injection.
In view of our findings, and those of others, showing the importance
of ADORA2B activation in penile erection, it is possible that
ADORA2B agonists could serve a useful therapeutic role in
vasculogenic ED. Recently a novel specific ADORA2B agonist,
BAY 60-6583, has been shown to have a therapeutic role in
myocardial ischemia by activation of ADORA2B, suggesting that it
may also have a potential therapeutic role in ED.46

Concluding Remarks
An unexpected erectile side effect of sildenafil on erectile
physiology drew more attention toward NO as a vasodilator in
the process of penile erection, and a recently discovered,
unexpected priapic phenotype of adenosine deaminase deficient
mice enhances the importance of adenosine as a key regulatory
of erectile status. Adenosine and NO share multiple features,
making them excellent contributors to erectile physiology. First,
both are well-known potent vasodilators and neurotransmitters.
Second, both have a very short half life. Third, both induce the
synthesis of cyclic nucleotide second messengers and penile
erection. Specifically, adenosine functions through G protein
coupled receptors to modulate adenylyl cyclase and the synthesis
of cAMP. NO functions through guanylyl cyclase to induce the
synthesis of cGMP. Finally, adenosine-mediated cAMP induction and NO-mediated cGMP induction are capable of inducing
protein kinase A and protein kinase G, respectively, resulting in
decreased calcium/calmodulin-dependent myosin light chain
phosphorylation and enhanced smooth muscle relaxation. In
conclusion, neuronal activationmediated ATP release, leading
to increased adenosine and neuronal nitric oxide synthases

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activation-mediated NO release, independently contributes to

the initiation of penile erection. Subsequently, sheer stress
mediated ATP release, resulting in increased adenosine, contributes to maintenance of penile relaxation. Eventually, continuous
production of adenosine mediated by shear stress leads to
sustained and potent penile erection via direct effect on vascular
smooth muscle cells by induction of cAMP and indirect activation of eNOS via phosphatidylinositol 3-kinases-AKT adenosine
in endothelial cells. A model depicting the actions of adenosine
and NO in erectile physiology is presented in Figure 2.

Disclosures
None.

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Adenosine Signaling: Good or Bad in Erectile Function?

Jiaming Wen and Yang Xia
Arterioscler Thromb Vasc Biol. 2012;32:845-850
doi: 10.1161/ATVBAHA.111.226803
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