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.
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 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, 19, 20, 21, 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, 27, 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, 30, 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 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 μm), 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, 40, 41, 42, 43, 44, 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 in hypoxia is primarily because of increased K+-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 (∼10 μm), 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 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, 59, 60, 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 long-lived 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, 68, 69, 70, 71
AGEs are implicated in the pathophysiology of both micro- and macrovascular complications.72 They can induce oxidative stress in 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 cholinergic-nitrergic phenotype to AGEs, induces apoptosis in a NO-dependent 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, 83, 84 An AGE-breaker, 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, 93, 94 angiotensin-converting enzyme inhibitors,91, 94, 95, 96, 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.
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.
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The authors wish to thank the European Society for Sexual Medicine (ESSM) for continuing support.
The authors declare no conflict of interest.
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Cellek, S., Cameron, N., Cotter, M. et al. Pathophysiology of diabetic erectile dysfunction: potential contribution of vasa nervorum and advanced glycation endproducts. Int J Impot Res 25, 1–6 (2013). https://doi.org/10.1038/ijir.2012.30
- advanced glycation endproducts
- diabetes mellitus
- erectile dysfunction
- nitric oxide
- vasa nervorum
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