1. International Journal of Impotence Research (2013) 25, 1–6
& 2013 Macmillan Publishers Limited All rights reserved 0955-9930/13
www.nature.com/ijir
REVIEW
Pathophysiology of diabetic erectile dysfunction:
potential contribution of vasa nervorum and advanced
glycation endproducts
S Cellek1, NE Cameron2, MA Cotter2 and A Muneer3
Erectile dysfunction (ED) due to diabetes mellitus remains difficult to treat medically despite advances in pharmacotherapeutic
approaches in the field. This unmet need has resulted in a recent re-focus on the pathophysiology, in order to understand the
cellular and molecular mechanisms leading to ED in diabetes. Diabetes-induced ED is often resistant to PDE5 inhibitor treatment,
thus there is a need to discover targets that may lead to novel approaches for a successful treatment. The aim of this brief review is
to update the reader in some of the latest development on that front, with a particular focus on the role of impaired neuronal blood
flow and the formation of advanced glycation endproducts.
International Journal of Impotence Research (2013) 25, 1–6; doi:10.1038/ijir.2012.30; published online 23 August 2012
Keywords: advanced glycation endproducts; diabetes mellitus; erectile dysfunction; hypoxia; microvessel; nitric oxide; vasa
nervorum
INTRODUCTION
Penile erection is the result of relaxation of smooth muscle in the
cavernous body and associated blood vessels.1 Smooth muscle
relaxation is mediated primarily by nitric oxide (NO), which is a
gaseous and labile mediator, yet one of the most potent
endogenous smooth muscle relaxants. NO is synthesised by
neuronal NO synthase (nNOS) in the autonomic postganglionic
parasympathetic nerves (nitrergic nerves)2,3 and by endothelial
nitric oxide synthase in the endothelium lining the blood vessels
and cavernosal sinusoids. Nerve impulses in response to sexual
stimulus are carried from the spinal cord to the hypogastric plexus
where the cell bodies of the nitrergic nerves are located. Once
activated, the nitrergic neurones within the hypogastric plexus
transmit action potential through their axons to the penile
vasculature. These nitrergic axons then release high quantities of
NO on to the nearby smooth muscle cells. NO diffuses rapidly into
the smooth muscle cells, causing relaxation by increasing the
intracellular concentrations of cGMP. The relaxation of the
cavernosal and arterial smooth muscle results in an increase in
blood flow into the penis. In turn, this causes shear stress on the
endothelial lining, which promotes phosphorylation and
prolonged activation of endothelial nitric oxide synthase leading
to long-lasting release of NO from the endothelium to maintain the
smooth muscle relaxation.4 As the intracavernosal pressure reaches
the level of the systemic arterial blood pressure, the subtunical
venules are compressed, which results in a rigid erection.
Diabetes mellitus is one of the predominant risk factors of
erectile dysfunction (ED) and also one of the most difficult to
treat.5,6 Approximately 50% of diabetic men will suffer from ED
within 10 years of the diagnosis.7 ED presenting in these men is
widely regarded as a manifestation of more systemic vascular
disease and is likely to precede a coronary event by 5 years.8,9
Combined with the prevalence of obesity and metabolic syndrome
in these men, it is apparent that disease progression is likely to
reduce the efficacy of conventional pharmacotherapeutic options
for the treatment of ED in diabetic men. This has meant that
diabetic men form a large group of patients undergoing end-stage
treatment in the form of penile prosthesis surgery.
Our knowledge regarding the pathophysiology of ED in
diabetes has gradually increased since the 1990s. As NO is the
main erectile mediator, the field has focussed on how diabetes
alters the nitrergic and endothelial NO function. The aim of this
paper is to update the reader with some of the latest development
on that front, with a particular focus on the role of impaired
neuronal blood flow, and the formation of advanced glycation end
products.
A NEED FOR TEMPORAL ANALYSIS
The tone of penile vascular and cavernosal smooth muscle is
regulated by vasodilators such as NO and vasoactive intestinal peptide, and by vasoconstrictors such as noradrenaline and endothelins.
An imbalance in favour of the vasoconstrictors has been demonstrated in both type 1 and 2 diabetes.9,10 Such an imbalance seems
to be caused by several factors, all playing equal roles, such as
decreased NO production from either nitrergic nerves or endothelium,10 low responsiveness of the smooth muscle to vasodilators,1
upregulation of the receptors for vasoconstrictor mediators such as
endothelin11 and increased vasoconstrictor production and/or
release and hyper-responsiveness to vasoconstrictors.12
It is important to study the progression of ED in a temporal
fashion in order to gain a better understanding of the
1
Department of Translational Medicine, Cranfield Health, Cranfield University, Bedfordshire, UK; 2School of Medical Sciences, University of Aberdeen, Aberdeen, UK and 3Institute
of Urology, University College London, London, UK. Correspondence: Dr S Cellek, Department of Translational Medicine, Cranfield Health, Cranfield University, Bedfordshire, MK43
0AL, UK.
E-mail: s.cellek@cranfield.ac.uk
Received 8 May 2012; revised 2 July 2012; accepted 20 July 2012; published online 23 August 2012

2. Vasa nervorum and AGEs in diabetic ED
S Cellek et al
2
pathophysiology of the condition. Although such longitudinal
studies investigating the mechanisms at different time points
of the disease are few,13 they provide invaluable information into
our understanding of diabetic ED. Similar longitudinal studies
from other fields within or outside the diabetes field14 also have
been extremely useful in broadening our comprehension of
pathophysiological events.
THE STORY BEGINS WITH HYPERGLYCAEMIA
At the early stages of diabetes, before the patient has symptoms of
any complications such as ED and may not even be aware of the
underlying diagnosis and high blood glucose levels, there are two
very important factors that trigger the cascade of events: high
blood glucose and low insulin (low insulin concentration in Type 1
diabetes and low insulin action due to receptor resistance in
Type 2). The effect of high glucose on endothelial NO-dependent
vasodilation has been debated: using isolated human blood vessels,
high glucose concentrations have been shown to have varying
effects on endothelial NO-dependent relaxations depending on the
type of the vascular bed.15,16 In humans, early reports have shown
that elevation of blood glucose concentrations does not affect the
forearm blood flow.16,17 Later, it has been found that the reason for
glucose-induced vasodilatation could be because of increased
insulin levels as a direct response to glucose; insulin is known
to elicit vasodilation directly.17 When such studies were repeated
using agents like octreotide to inhibit insulin secretion, hence
removing the influence of insulin on vasodilation, high glucose
concentrations caused an acute and transient reduction in
endothelium-dependent vasodilation.18–22 This has been attributed to increased vasoconstrictor mediators22 and decreased
endothelial NO production23 as a direct response to hyperglycaemia. Therefore we can deduce that acute and direct effect
of hyperglycaemia could be a transient reduction in blood flow in a
healthy individual. In diabetic patients or individuals with impaired
glucose tolerance, the recovery from reduced vasodilation has been
shown to be delayed.20,24
Although high glucose concentrations impair nitrergic
function acutely and reversibly in vitro,24,25 ED occurs much later
in diabetic animal models.5,13,26–28 These observations have led the
researchers to conclude that endothelial dysfunction precedes
nitrergic dysfunction. There seems to be a lag period between
endothelial and ED; the latter coinciding with nitrergic dysfunction.
In perspective, it takes a minimum of 4 weeks for a rat to develop
erectile and nitrergic dysfunction,13,27,28 whereas endothelial
dysfunction can potentially develop in days as a direct
consequence of hyperglycaemia, as mentioned above. So one
question arising is: ‘What pathophysiological role could endothelial
dysfunction play in the early stages of the development of ED?’.
One potential answer comes from another area of the diabetes
field, the study of blood flow to peripheral nerves. Within days of
induction of experimental diabetes, blood flow to major nerve
trunks such as sciatic nerve has dropped.13,27,29–31 Recently such a
dramatic decrease in blood flow has also been shown in the
superior cervical32 and in the major pelvic ganglia of diabetic rats.33
The latter is equivalent to hypogastric plexus in the human34 and
contains the cell bodies of the neurons that innervate the
urogenital organs, including penis. Thus it is plausible that an
early decrease in blood flow to the ganglia in response to the
diabetic state, including elevated glucose, may be the first step
triggering a series of events.
THE ROLE OF THE VASA NERVORUM
The ganglia where the cell bodies of the autonomic nerves are
located are surrounded by small-diameter blood vessels (arterioles
and venules) known as vasa nervorum, which supply the blood
necessary for the function of the neurons. All nerve trunks, from
International Journal of Impotence Research (2013), 1 – 6
large ones such as the sciatic nerve to small ones such as the
cavernous nerve, have their own vasa nervorum. Earlier studies
have shown that vasa nervorum of the peripheral nerve trunks can
be divided into three groups: epineurial, perineurial and
endoneurial.35 Epineurial and perineurial blood vessels form a
complex network known as the epineurial plexus.35 The epineurial
plexus has prominent arteriovenous shunts, supplies the
endoneurial vascular compartment and is innervated by
autonomic nerves such as sympathetic and peptidergic nerves.36
However, such detailed information is not available for the vasa
nervorum of the autonomic ganglia, although ganglia have a
much greater metabolic demand than peripheral nerve trunk.35
Whether the vasa nervorum of autonomic ganglia can be divided
into sub-compartments like in the peripheral nerve trunk is not
known. Moreover, details on the innervation of ganglion vasa
nervorum are sparse. We have recently shown that the rat major
pelvic ganglia are surrounded by numerous small diameter blood
vessels (20-120 mm), which are innervated by noradrenergic and
nitrergic nerve fibres.37 A drop in blood flow by as much as 50% is
observed in the autonomic ganglia as early as 1 week after
diabetes induction,32,33 although such an early decrease in blood
flow is not associated with ED initially. Thus drawing parallels with
vasa nervorum in nerve trunks, it is likely that such a reduction in
perfusion would cause ganglionic neurons to be exposed to a
hypoxic environment.
CONSEQUENCES OF HYPOXIA IN AUTONOMIC GANGLIA AND
AXONS
Hypoxia can trigger several neuronal events both in the cell body
and axon of the neuron: disturbances in membrane conductivity,
impaired nerve conduction and action potential generation, and
decreased axonal transport. It is therefore not surprising that
nitrergic function in the isolated human corpus cavernosum
deteriorates in hypoxic conditions.38 However it should be noted
that the corpus cavernosum does not contain the neuronal cell
bodies of the nitrergic nerves. To date, the effect of hypoxia on
nitrergic neurons obtained either from human hypogastric plexus
or rat major pelvic ganglia has not been studied. In the absence of
direct evidence, inferences can be made from studies in other
parts of the peripheral and in the central nervous systems. Acute
hypoxia or ischaemia alters the expression of endothelial nitric
oxide synthase and nNOS in the blood vessels and central
neurons, respectively.39–45 In the nodose ganglion, which primarily
holds sensory neurons, acute hypoxia increases nNOS protein
expression 2-4 folds.45 Upregulation of nNOS in the central
neurons is thought to be a compensatory mechanism to replenish
the blood flow by vasodilation and neovascularization. Whether a
similar phenomenon occurs in the autonomic ganglia remains to
be investigated.
Although acute hypoxia may increase nNOS expression transiently, nitrergic function deteriorates as the hypoxia is prolonged. In
chronic hypoxia models where animals were exposed to hypoxia
for extended periods, a significant decrease in nNOS expression
and NO production has been shown for nerves innervating the
cerebral arteries46 and the central neurons.47 Interestingly chronic
bladder outlet obstruction decreases nNOS expression in the
intramural neurons of the bladder, which has been attributed to the
chronic hypoxia caused by the urethral ligation.48,49 Although
sympathetic neurons have received greater attention than nitrergic
neurons within the ganglia, existing studies suggest that chronic
hypoxia causes a nitrergic–sympathetic imbalance in favour of
sympathetic system, which may contribute to conditions associated
with chronic hypoxia such as hypertension and chronic respiratory
failure.49
Acute and chronic hypoxia are associated with reduced nerve
conduction velocity and neuronal action potential generation.50
In the central neurons, the reduction of nerve cell excitability
& 2013 Macmillan Publishers Limited

3. Vasa nervorum and AGEs in diabetic ED
S Cellek et al
3
reversible phase
DIABETES
hyperglycemia
dyslipidemia
Axonal
transport
defect
Vasoconstriction
in vasa nervorum
Endothelial
dysfunction in
the penis
Hypoxia
in ganglia
Nerve
conduction
defect
NO
production
at nerve
terminals
irreversible phase
nNOS
accumulation
in cell body
nNOS
depletion at
nerve
terminals
Nitrergic
degeneration
Irreversible
erectile
dysfunction
Point of
no
return
Endothelial NO
production in
penis
ED symptoms
AGEs
TIME
Figure 1. The schematic representation of temporal effect of microvascular deficit and advanced glycation endproducts (AGEs) on erectile
function with particular emphasis on nitrergic nerves.
in hypoxia is primarily because of increased K þ -conductance.
Thus, the nerve cells are hyper-polarised and the input resistance
reduced, causing higher threshold and reduction of synaptic
potentials.51,52 In the peripheral nerves, hypoxia elicited
reductions in both sensory and motor conduction velocities
similar to those observed in diabetic animals.53
Another consequence of hypoxia on the central and peripheral
nerves is a reduction in axonal (axoplasmic) transport. The
neurons transport the proteins, lipids, vesicles and organelles to
distal parts of their axons via axonal transport. Considering that an
axon can be as long as 1-2 m (for example, in the sciatic nerve
trunk) compared with its neuronal body (B10 mm), an efficient
two-way transport system akin to a very busy highway is required
to meet the metabolic and functional needs of a neuron.
Disruption of axonal transport can result in acute accumulation
of proteins in the cell body, mitochondrial dysfunction in the distal
parts of the nerve and loss of neuronal function which can
eventually lead to axonal and/or neuronal degeneration. Diabetes
is known to alter axonal transport.54 Rats exposed to hypoxia for
up to 24 h have increased nNOS protein in the peripheral
ganglia.39 Interestingly, patients with chronic mountain sickness
who suffer from ‘‘burning feet and hands’’ sensation at high
altitudes (low oxygen) exhibited mild sensory neuropathy which
was attributed to the disruption of axonal transport.55 We have
previously shown that nNOS protein is depleted in the axons and
accumulates in the autonomic ganglia of diabetic rats.13,14
Overall it can be hypothesised that, hypoxia secondary to
diabetes-induced dysfunction of vasa nervorum supplying the
nerve trunks and ganglia alters neuronal electrophysiology and
axonal transport (Figure 1). Such effects can happen acutely and
are often reversible as noted in both animal and human studies
mentioned above. For example, patients who return to lower
altitude after a trip in the mountains report improvement in their
‘burning feet and hands’ symptoms within weeks.55
CONSEQUENCES OF NERVE DYSFUNCTION AND AXONAL
TRANSPORT DEFECT
Reduced conduction velocity develops in motor and sensory
nerves within 2–3 weeks of diabetes induction in rats.29 During
this phase, there are no obvious structural alterations to the
nerves and the deficit is largely reversible on the establishment of
& 2013 Macmillan Publishers Limited
normoglycaemia with insulin.56,57 A somewhat similar
phenomenon can be observed in patients who were newly
diagnosed with Type 1 or 2 diabetes.58–61 Autonomic nerves
follow a similar pattern: nitrergic dysfunction, nNOS depletion in
the axons and accumulation in the ganglia can be reversed using
insulin within the first 10 weeks of diabetes in rats, whereas there
is no loss of neurons.13,14 We have previously coined the term
‘reversible phase’ followed by ‘a point of NO return’ (Figure 1).26
Thus, it is important to diagnose and start treatment within the
first few years of human diabetes. The two largest trials in the
diabetes field: The United Kingdom Prospective Diabetes Study
(UKPDS62) and the Diabetes Control and Complications Trial
(DCCT63) have answered the question of whether blood glucose
control is beneficial for people with diabetes with respect to the
development of complications. It definitely is. Although improved
glycaemic control reduces the incidence of diabetic complications,62,63 physiological levels of control are difficult to achieve.
In addition, as diabetes duration increases, complications develop
and confounders such as chronic hypertension and dyslipidaemia
contribute to the complications, thus lessening the beneficial
impact of tight glycaemic control.64
HOW DO THE REVERSIBLE CHANGES BECOME IRREVERSIBLE?
Data suggest that this could be because of several factors:
Primarily, the ongoing impact of hypoxia and nerve dysfunction;
secondarily, owing to the accumulation of advanced glycation
endproducts (AGEs). AGEs are adducts formed on proteins and
lipids following non-enzymatic glycation and oxidisation after
exposure to aldose sugars and their metabolites. Similar adducts
may be formed by lipid-oxidation products. AGEs are formed
naturally in human body, and they are also ingested in food as a
result of cooking processes. They accumulate with age on longlived proteins such as collagen. Diabetes is considered an
accelerated form of aging65 because of this elevated AGE
accumulation.66 In addition, it is becoming increasingly apparent
that relatively rapid intracellular AGE formation, primarily as a
result of increased methylglyoxal levels resulting from triose
metabolism, has marked effects in the pathophysiology of diabetic
complications, including endothelial dysfunction.67–71
AGEs are implicated in the pathophysiology of both micro- and
macrovascular complications.72 They can induce oxidative stress in
International Journal of Impotence Research (2013), 1 – 6

4. Vasa nervorum and AGEs in diabetic ED
S Cellek et al
4
the cells either by binding to specific receptors (for example,
receptor for AGEs), or as a result of their chemical reactions.73
AGEs have been shown to reduce endothelium-dependent
vasorelaxation by altering the endothelial NO synthase
synthesis74,75 and have been associated with impaired
endothelium-dependent vasodilation in Type 2 diabetic
patients.76 AGEs accumulate both in the penis77,78 and major
pelvic ganglia during diabetes.13,26,79 Exposure of human
neuroblastoma cells, which are differentiated into cholinergicnitrergic phenotype to AGEs, induces apoptosis in a NOdependent manner.79 It has also been demonstrated that
receptor for AGEs expression is enhanced by ischaemia in the
heart80 and brain.81 Although the effect of AGEs in combination
with hypoxia have not been studied specifically in nitrergic
neurons, it is plausible that under hypoxic conditions the
detrimental effect of AGEs may be enhanced. Thus, hypoxia,
owing to microvascular defects in the ganglia, combined with the
cytotoxic effects of accumulating AGEs might be specifically
detrimental to nitrergic neurons. The death of nitrergic neurons
would result in irreversible decrease in neuronal numbers in the
ganglia as those neurons are not able to replicate themselves or
regenerate. Such a loss of neurons would inevitably push the
pathology into the irreversible phase (Figure 1).
Studies with inhibitors of AGE formation, such as the reactive
carbonyl scavenger, aminoguanidine, have shown several beneficial effects in experimental diabetes. Thus, diabetic deficits in
NO-mediated endothelium-dependent vasorelaxation were prevented, peripheral nerve conduction velocity and blood flow was
improved, and several studies have shown prevention and
reversal of ED in the early stages of diabetes.78,82–84 An AGEbreaker, ALT-711 (alagebrium) was also able to reverse the ED in
diabetic rats.85 It should be noted that ALT-711 has been
suggested to have secondary effect on oxidative stress as it is a
metal chelator compound.86 Nevertheless, the removal of already
formed AGEs from the body remains a potentially important
therapeutic approach.
WHAT ARE THE TREATMENT OPTIONS WITHIN VASCULAR
HYPOTHESIS?
As the hypoxia caused by microvascular deficit is the trigger
leading to a series of events that eventually cause irreversible
damage (Figure 1), would the reversal of hypoxia be clinically
beneficial? In diabetic patients who suffer from painful
peripheral neuropathy, PDE5 inhibitors have elicited acute relief
of pain87 this has been attributed to the vasodilator effect of
PDE5 inhibitors in the vasa nervorum supplying the nerves,
although the situation here is complex to interpret as NO has
been implicated in pain processing.88 Similarly, PDE5 inhibitors
have been shown to be efficacious in relieving lower urinary tract
symptoms related to benign prostatic hyperplasia,89 which could
be attributed to the vasodilator effect of PDE5 inhibitors in the
vasa nervorum supplying the nerves and ganglia innervating the
urinary bladder.
Cholesterol-lowering drugs such as statins,90,91 vasodilators
such as alpha-1 adrenoceptor antagonists, beta-2 adrenoceptor
agonists,92–94 angiotensin-converting enzyme inhibitors,91,94–97
angiotensin receptor blockers,98 endopeptidase inhibitors99 and
gene therapy such as vascular endothelial growth factor
(VEGF100,101) have been shown to be beneficial in correcting
nerve blood flow and function in diabetes in pre-clinical and
clinical studies. Other approaches such as thiamine, PARP
inhibitors and SOD/catalase mimetics to relieve the oxidative
stress and restore endothelial function can also be of potential
benefit to restore blood flow into the vasa nervorum.102 Novel
vasodilator approaches specific to vasa nervorum may be of
potential therapeutic value in the future.
International Journal of Impotence Research (2013), 1 – 6
CONCLUSIONS
It is highly plausible that a microvascular deficit in the vasa
nervorum of nerve trunks and ganglia is a major trigger for a
cascade of events that eventually lead to diabetic neuropathy and
autonomic neuropathy. ED is a consequence of these events and if
not treated early may become irreversible. Restoring diminished
blood flow to the vasa nervorum as early as possible before
irreversible changes such as fibrosis and neuronal degeneration
occur should be a key aim of medical management of diabetic
neuropathy. Clearly, we still have several challenges to meet:
improving our understanding how the vasa nervorum tone is
regulated by endothelial and neuronal mediators, and the
development of non-invasive blood flow measurement techniques in human vasa nervorum to further test the validity of this
hypothesis.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
The authors wish to thank the European Society for Sexual Medicine (ESSM) for
continuing support.
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