Emerging Role for TNF-α in Erectile Dysfunction

Abstract

Introduction

A role for cytokines in the pathophysiology of erectile dysfunction (ED) has emerged. Cytokines induce genes that synthesize other peptides in the cytokine family and several mediators, such as prostanoids, leukotrienes, nitric oxide, bradykinin, reactive oxygen species, and platelet-activating factor, all of which can affect vascular function. Consistent with the fact that the cavernosal tissue is a complex extension of the vasculature, risk factors that affect the vasculature have been shown to affect cavernosal function as well. Accordingly, the penile tissue has been recognized as an early sentinel for atherosclerosis that underlies coronary artery disease and cardiovascular diseases (CVD).

Aim

To review the literature pertaining to the role of tumor necrosis factor-alpha (TNF-α) in ED.

Methods

PubMed search for pertinent publications on the role of cytokines, particularly TNF-α, in CVD and ED.

Main Outcome Measures

Clinical and experimental evidence demonstrates that TNF-α may play a role in ED.

Results

TNF-α has been shown to play an important role in CVD, mainly due to its direct effects on the vasculature. In addition, high levels of TNF-α were demonstrated in patients with ED. In this review, we present a short description of the physiology of erection and the cytokine network. We focus on vascular actions of TNF-α that support a role for this cytokine as a potential candidate in the pathophysiology of ED, particularly in the context of CVD. A brief overview of its discovery, mechanisms of synthesis, receptors, and its main actions on the systemic and penile vasculature is also presented.

Conclusions

Considering that ED results from a systemic arterial defect not only confined to the penile vasculature, implication of TNF-α in the pathophysiology of ED offers a humoral linking between CVD and ED.

The Physiology of Erection

Penile erection is determined by pressure changes in the cavernosal sinuses. The vasculature of the erectile tissue differs from most vascular beds as it is composed of arterioles and hollow blood-filled sinuses, both of which are lined with smooth muscle and endothelial cells [1-3]. In the absence of arousal stimuli, cavernosal vasoconstriction maintains the penis in the non-erect state. Contraction of the cavernosal smooth muscle, mainly in response to norepinephrine (NE) released from sympathetic nerve terminals, narrows the arteriolar lumen and sinusoidal cavities, restricting blood flow to maintain low intracavernosal pressure and a non-erect (flaccid) penis [1-3]. During sexual arousal or nocturnal tumescence, the release of nitric oxide (NO) (predominantly through the activation of neuronal nitric oxide synthase [nNOS] in nonadrenergic noncholinergic [NANC] nerves and local endothelial cells [endothelial nitric oxide synthase, eNOS]) stimulates smooth muscle relaxation [1-3]. The resulting dilation of the cavernosal arterioles and sinuses results in increased blood flow (driven by the force of the arterial blood pressure) and a subsequent rise in intracavernosal pressure. The erectile response ensues as the force of the elevated pressure expands the outer tunica albuginea of the penis, resulting in the increased penile length and diameter characteristic of erection.

Although various vasodilators have been implicated in the erectile response, NO is thought to be the principal stimulator of cavernosal vasodilation and penile erection [4-6]. NO is formed from the precursor amino acid, L-arginine, by enzymatic action of NOS, which exists as three main isoforms: nNOS, inducible nitric oxide synthase, and eNOS. All three isoforms have been detected in the penis; nevertheless, nNOS and eNOS are constitutive NOS enzymes expressed in penile tissues [5,7-9]. Upon its release, NO diffuses locally into adjacent smooth muscle cells of the corpus cavernosum and binds to soluble guanylyl cyclase, which catalyzes the conversion of guanosine triphosphate (GTP) to 3′,5′-cyclic guanosine monophosphate (cGMP). This cyclic nucleotide then activates protein kinase G, also known as cGMP-dependent protein kinase I, which decreases cytosolic calcium (Ca²⁺) by various mechanisms. The decay in cytosolic Ca²⁺ concentration induces relaxation of the vascular and cavernosal smooth muscle cells, leading to dilation of arterial vessels, increased blood flow into the sinuses of the corpora cavernosa, and penile erection [10,11].

NE, released from sympathetic nerve terminals, initiates contraction via a rise in the concentration of cytoplasmic Ca²⁺ and triggers smooth muscle contraction and flaccidity. Increased intracellular Ca²⁺ enhances the binding of Ca²⁺ to calmodulin, leading to activation of myosin light chain kinase and phosphorylation of the myosin light chain (MLC₂₀) of myosin II. The extent of MLC₂₀ phosphorylation or force of contraction induced by agonist stimulation is normally higher than that predicted by the actual Ca²⁺ concentration in the cell, the so-called Ca²⁺ sensitization process. Activation of the Ca²⁺-sensitizing pathway is regulated by Ras homolog gene family (Rho), member A (RhoA), a small G-protein from the Rho family that is activated upon the binding of GTP. Activation of RhoA, which is facilitated by Rho-specific guanine nucleotide exchange factors, stimulates downstream effectors, such as Rho kinase, or ROCK. Activated ROCK phosphorylates the regulatory subunit of myosin light chain phosphatase and inhibits its activity, inhibiting MLC₂₀ dephosphorylation and facilitating smooth muscle cells contraction and flaccidity [10,11]. The importance of ROCK in the Ca²⁺ sensitization of corpus cavernosum smooth muscle cells and maintenance of penile flaccidity is well established [11-13]. All the components of RhoA/ROCK signaling pathway (RhoA, phosphatase inhibitor CPI-17, myosin phosphatase regulatory [MYPT-1] and catalytic [PP1delta] subunits, ROCK isoforms) are expressed in corpora cavernosa from several species and ROCK inhibition increases corpus cavernosum pressure in in vivo models [10,11]. Increased ROCK activity also plays critical roles in certain types of erectile dysfunction (ED) [14-19]. Rho-dependent pathways are activated by several stimuli and mediate cellular functions other than vascular smooth muscle cells contraction including actin cytoskeleton organization, cell adhesion, proliferation, migration, and inflammation, all of which are associated with vascular remodeling [20,21]. Recent evidence indicates that RhoA/ROCK is involved in the progression of target organ damage induced by vasoactive hormones, such as angiotensin II (Ang II) and aldosterone [22,23].

Based on the above information, it is reasonable to postulate that any substance that decreases relaxation mechanisms or increases contractile mechanisms in cavernosal smooth muscle cells may be a causative agent to the development of ED. In this sense, several cytokines, particularly tumor necrosis factor-alpha (TNF-α), appear as the most prominent candidate to the pathophysiology of ED due to its known effects on the vasculature.

Cytokines

Cytokines are soluble hormone-like proteins that provide communication between cells and the external environment. It is a term that comprises different protein families, such as lymphokines, monokines, interleukins (IL), colony-stimulating factors, interferons, chemokines, and TNF [24,25]. Although cytokine actions and interactions are extraordinarily complex and it seems to defy a simple understanding of their physiological function, some broad basic properties are commonly shared among cytokines: (i) pleiotropy, where a single cytokine can act on many different types of cells rather than a single cell type; (ii) redundancy, comprising a similar function that can be stimulated by different cytokines; and (iii) multifunctional referring to the fact that the same cytokine may be able to regulate several different immune functions [24].

Cytokines are secreted by white blood cells in the body in response to inflammatory stimuli [24-26]. However, it is now clear that other cells and tissues not only produce but are often major targets of cytokine effects. Among these tissues is the vascular endothelium, and a large body of evidence suggests that cytokines induce a variety of structural and functional alterations in endothelial cells (often called “endothelial activation”) and that cytokine-endothelial interactions may play important roles in immunity, inflammation, and vascular injury [27-29].

Furthermore, several reports have demonstrated that cytokines modulate the tonus of the vasculature in different vascular beds [30,31], and the vascular response appears to be related to the balance between all the vasoactive factors released under the influence of cytokines. Thus, regional differences in release and responsiveness to these factors appear to contribute to the dilator or constrictor response observed within a specific vascular bed [32]. In addition, the presence of a low-grade inflammatory process is associated with many cardiovascular diseases (CVD) and, accordingly, cytokines levels, such as TNF-α, are increased in response to inflammation and contribute to the changes in vascular reactivity observed in CVD [29,33-35].

TNF-α: Its Receptors, and Signaling Pathway

TNF-α, named for its ability to cause rapid necrotic tumor regression [36], is the founding member of the TNF ligand superfamily, which is known to have pleiotropic functions including cell proliferation, differentiation, activation, and apoptosis [37]. TNF-α is primarily produced by macrophages, lymphocytes, neutrophils, keratinocytes, and fibroblasts during acute inflammatory reactions [38]. However, it has been demonstrated that TNF-α is produced in cardiac myocytes, smooth muscle cells, and endothelial cells in response to endotoxin independent of the presence of inflammatory cells in ex vivo and in vitro cardiac studies [39,40]. Its synthesis is initiated by the transcriptional activation of the TNF-α gene, which is largely driven by several nuclear factor-kappa B (NF-κB) responsive elements in the 5′ promoter region [41]. Currently, two isoforms of TNF (TNF-α and TNF-β) have been identified and share similar inflammatory activities [42]. TNF-α is the smaller and more abundant of the two peptides, and TNF-β (first described as lymphotoxin-α) [43] is less abundant, and is thought to be produced mainly by T-cells. TNF-β will not be discussed further in this review. TNF-α receptors (TNFRs) signal as homotrimers, and can exist either as membrane-bound or as truncated soluble forms [44]. Two distinct surface receptors mediate the effects of TNF-α, TNFR-1 (p55), and TNFR-2 (p75), both receptor subtypes are found in endothelial cells [45], smooth muscle [46], human and rat cardiac myocytes [47,48]. Furthermore, gene expression of TNFR-1 has been demonstrated in cavernosal tissue [49]. The wide repertoire of signaling responses elicited by TNF results from the ability to recruit a range of adapter proteins to the receptor. Both TNFRs and associated adapter proteins contain various defined regions or motifs that have been shown to elicit specific signaling events (Figure 1). Usually, the first protein recruited to TNFR1 activation is TNFR1-associated death domain protein (TRADD), which serves as a platform to recruit at least three additional mediators, receptor-interacting protein 1, Fas-associated death domain protein and TNF-receptor-associated factor 2 (TRAF2) [50-53]. TRAF2 plays a central role in early events, common to TNFR1 and TNFR2, that lead to IκB kinase (IKK) and mitogen-activated protein kinase (MAPK) activation. Structural and biochemical analysis of the TRADD–TRAF2 complex reveals that TRAF2 has a higher affinity for TRADD than it has for TNFR1 or TNFR2 [52,54]. This might explain why TNF-α is a better activator of TNFR1, which uses TRADD as an adaptor, than TNFR2, which does not interact with TRADD. NF-κB activation represents one of the most central proinflammatory responses elicited by TNF-α, particularly in endothelial cells [55]. NF-κB is regulated primarily by phosphorylation of inhibitory proteins, the IκBs, which retain the transcription factor in the cytoplasm of nonstimulated cells [56]. In response to TNF-α and other agonists, the IκBs are phosphorylated by the IKK complex, resulting in their ubiquitination, degradation, and nuclear translocation of the freed NF-κB [56]. Once in the nucleus, NF-κB transcriptional activity can be modulated further through phosphorylation by various protein kinases that are TNF-α responsive, such as the p38 subgroup of MAPK, providing a point for cross talk with other signaling pathways. Although other signaling pathways are activated by TNF-α, such as MAPK, PI-3 Kinase/Akt, and sphingomyelinase, detailed discussion on this topic is beyond the scope of this review (more information about this topic can be obtained in comprehensive reviews [38,52,55,57-60]).

Figure 1.

Illustration demonstrates the sequential events in the activation of TNFR1 and TNFR2 receptors by tumor necrosis factor-alpha (TNF-α). Usually, TNFR1-associated death domain protein (TRADD) is the first recruited protein after TNFR1 receptor activation, which acts like an anchor of at least three additional mediators: receptor interaction protein 1 (RIP1), TNF-receptor-associated factor 2 (TRAF2), and Fas-associated death domain protein (FADD). TRAF2 stimulates antiapoptotic and inflammatory pathways, whereas FADD stimulates caspases inducing apoptotic and anti-inflammatory effects. TRAF2 is also recruited by TNFR2 receptor with TNF-receptor-associated factor 1 (TRAF1) causing inflammatory and antiapoptotic effects.

TNF-α Actions on the Vasculature

TNF-α is an important contributor to many CVD, such as myocardial ischemia–reperfusion injury, chronic heart failure, atherosclerosis, and sepsis-associated cardiovascular disorders [61-63].

Endothelial dysfunction is a key event in the pathophysiology of ED and, importantly, endothelial function is impaired in the presence of increased oxidative stress and inflammatory conditions [64]. The vascular endothelium is a major target for the actions of TNF-α in these diseases, in which TNF-α plasma levels are significantly elevated. Administration of TNF-α in vivo induces impairment of endothelium-dependent vasorelaxation in a variety of vascular beds and decreases the release of NO [65]. TNF-α has the ability to increase arterial reactive oxygen species generation, which likely accounts for some of the reduction in NO levels. Moreover, TNF-α suppresses eNOS expression by inhibiting the gene promoter activity [66,67], predominantly through destabilization of eNOS mRNA in endothelial cells [68]. In addition to its effects on endothelial function, a substantial proatherogenic role for TNF-α has recently been demonstrated [69]. The presence of TNFR1 in the vascular wall causes atherosclerosis [69].

In endothelial cells, TNF-α not only induces inflammatory gene transcription but also activation of RhoA and ROCK [70]. ROCK activation plays a role in TNF-α-induced increases in junctional permeability [71,72], as well as in TNF-α-induced actomyosin rearrangement and apoptosis [73]. Additionally, pharmacological inhibition of ROCK as well as dominant negative RhoA overexpression dramatically reduced TNF-α-induced endothelial cell permeability and apoptosis [71,73]. Degradation of inhibitor kappa-B followed by translocation of NF-κB into the nucleus and activation of gene expression is essential in TNF-α signaling. In human umbilical cord vein endothelial cells, inhibition of RhoA reduces TNF-α-induced NF-κB binding to DNA, via blockade of NF-κB-translocation [74]. Finally, TNF-α leads to increased Ca²⁺ sensitivity, via activation of the RhoA/ROCK pathway, a mechanism that may contribute not only to TNF-α-induced airway hyperresponsiveness and hyperreactivity [75,76]. Conversely, inhibitors of ROCK also block TNF-α production by lipopolysaccharide-stimulated monocytes [77] and burn-injured cardiomyocytes [78]. ROCK inhibitors attenuate TNF-α-induced leukocyte infiltration by inhibiting both cytoskeletal rearrangement of endothelial cells [79] and by a suppressive effect on the functions of polymorphonuclear leukocytes and expression of inflammatory cytokines [77,80-82]. All together, these observations suggest that ROCK inhibitors may display anti-inflammatory properties, by blocking TNF-α actions.

ED and Markers of CVD (Inflammatory Mediators)

ED, defined as the inability to attain and/or maintain penile erection [83], is a multifactorial condition that is estimated to affect more than 150 million men worldwide, with this number expected to double by 2025 [84,85]. Considered a major public health problem, which seriously affects the quality of life of patients and their partners, ED becomes increasingly prevalent with age. The presence of chronic illness (e.g., CVD), as well as smoking, alcohol or drug abuse, and sedentary lifestyle are major risk factors for ED [84,86].

Traditionally, ED is thought of as an outcome of occlusive systemic vascular disease that occurs as a late consequence of atherosclerosis. Prospective results from the Massachusetts Male Aging Study [87] demonstrated that ED and coronary artery diseases (CAD) share common risk factors in humans. In addition, the prevalence of ED ranges from 42% to 75% in patients with established CAD [88-91] and severity of CAD is associated with the severity of ED [91-93]. Furthermore, Montorsi and coworkers [94] reported that CAD and atherosclerotic burden determine the rate of ED: it is low in acute coronary symptoms and one-vessel disease and high in chronic coronary syndrome. However, vasculogenic ED may result not only from occlusion of the cavernosal arteries by atherosclerosis (structural vascular ED), but also from impairment of endothelial function/smooth muscle relaxation (functional vascular ED) [95-97]. Current and emerging clinical studies show that the penile vascular bed may be indeed a sensitive indicator of early systemic endothelial cell and/or smooth muscle dysfunction. In other words, ED is considered an early clinical manifestation of generalized vascular disease and carries an independent risk for cardiovascular events [98-100]. While it is clear that ED is multifactorial, longitudinal population-based studies clearly demonstrate that cardiovascular risk factors such as hypertension, dyslipidemia, central obesity, and insulin resistance are major risk factors for vasculogenic ED [101]. Furthermore, clustering of these factors, as occurs in patients with metabolic syndrome, increases the risk for the development of ED even further [102,103].

Recent evidence points to a low-grade inflammatory process as an important pathophysiologic component of CVD. Accordingly, inflammatory markers are increased in patients with hypertension and metabolic disorders, and predict the development of CVD [104]. Patients with CVD present with increased expression and plasma concentration of several inflammatory mediators, which include C-reactive protein (CRP) and adhesion molecules, such as selectins (P-selectin, E-selectin, and L-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Moreover, increased plasma levels of the primary inflammatory cytokine TNF-α and of the secondary inflammatory cytokine IL-6, as well as ICAM-1, VCAM-1, E-selectin, von Willebrand factor (vWF), and CRP have been demonstrated in patients with hypertension [104]. High levels of inflammatory mediators are considered independent risk factors for the development of hypertension and may also be associated with increased risk of diabetes, CVD, and ED. Available evidence identifies inflammation as a common pathophysiologic mechanism linking ED, metabolic syndrome, and CAD [34,105-112]. Patients with ED also present with increased expression and plasma concentration of inflammatory markers and mediators, including CRP [34,106-108,110,111], adhesion molecules (P-selectin, ICAM-1, VCAM-1) [107,111], and cytokines (TNF-α, IL-6, IL-8, IL-18) [34,108,111]. Importantly, plasma levels of these inflammatory markers are significantly higher in patients with ED (vs. subjects without ED) matched for age and coronary risk score [109]. In addition, levels of inflammatory markers are also increased in men with ED but without cardiovascular risk factors or overt vascular damage [107]. Finally, sexual performance has also been negatively correlated with circulating levels of endothelial prothrombotic and inflammatory parameters such as fibrinogen, vWF, IL-1β, and IL-6 [34]. Therefore, therapeutic approaches to control vascular inflammation, particularly in patients with ED and CVD, may provide significant clinical benefits.

TNF-α and ED

Figure 2 illustrates the complex interplay between ED and CAD, where the incidence of ED and the levels of TNF-α are simultaneously correlated to age [84,113,114]. It is noteworthy that CAD appears right after ED and after the levels of TNF-α start to increase [87,89,94]. Thus, TNF-α may represent not only a common link between ED and CAD, but its increasing levels associated with ED may be a predictor of cardiovascular events.

Figure 2.

Graph demonstrates simultaneous increase in the levels of tumor necrosis factor-alpha (TNF-α), erectile dysfunction (ED) and coronary artery disease (CAD). Correlation between age and plasma TNF-α levels (straight line). The dashed line illustrates the correlation between the incidence of ED and age. The age range for the first clinical symptoms of CAD is indicated by the shaded area. Adapted results from references [70,75,80-82].

The association between low-grade inflammation and altered endothelial–prothrombotic state on one side and ED on the other in patients with and without CAD has been recently reviewed [34]. Several lines of evidence suggest that TNF-α plays a key role in inducing endothelial dysfunction. First, clinically stable heart transplant patients exhibit a strong positive relation between plasma TNF-α and impaired vascular response to acetylcholine [115]. Second, infusion of TNF-α alone impaired endothelial function in healthy subjects, whereas infusion of IL-6 did not [116]. Of major importance, TNF-α levels are increased in serum of patients with moderate to severe ED [34,112,117], and levels of TNF-α and endothelial–prothrombotic parameters are inversely associated with sexual performance [34].

Experimental studies have demonstrated that TNF-α knockout (KO) mice exhibit changes in cavernosal reactivity that would facilitate erectile responses: decreased responses to adrenergic nerve stimulation and increased NANC and endothelium-dependent relaxation that are associated with increased corporal eNOS and nNOS protein levels [118].

While eNOS is mainly involved in endothelium-dependent relaxation, nNOS is considered the major mediator of NANC relaxation in the penis [4-6]. Recently, it has been shown that TNF-α decreases nNOS expression in corpora cavernosa [49]. On the other hand, TNF-α knockout animals have increased nNOS expression in cavernosal tissue [118], which suggests that TNF-α down-regulates nNOS expression in cavernosal tissue (Figure 3). Accordingly, it has been demonstrated that TNF-α infusion significantly induces an increase in mean arterial pressure and a reduction in renal nNOS protein expression, within both the cortex and medulla from pregnant rats [119].

Figure 3.

Molecular mechanisms targeted by tumor necrosis factor-alpha (TNF-α) causing impairment of relaxation in the corpora cavernosa. During sexual arousal or sleep-related tumescence acetylcholine and nitric oxide (NO) are released from parasympathetic and nonadrenergic noncholinergic (NANC) nerves, respectively. Whereas acetylcholine causes NO generation by endothelial nitric oxide synthase (eNOS) activation on endothelial cells, neuronal nitric oxide synthase (nNOS) is responsible for NO production in NANC nerves. Upon its release, NO diffuses locally into adjacent smooth muscle cells of the corpus cavernosum and binds to soluble guanylyl cyclase, which catalyzes the conversion of guanosine trisphosphate (GTP) to 3′,5′-cyclic guanosine monophosphate (cGMP). TNF-α decreases eNOS and nNOS expression on endothelial cells and NANC nerves, respectively, causing impairment of cavernosal relaxation. Pro-inflammatory status is evoked by TNF-α, which induces adhesion molecules, nuclear factor-kappa B (NF-κB) and increases leukocyte migration. TNF-α induces changes in extracellular matrix deposition by smooth muscle cells and initiates a fibrotic state with reduced elasticity and compliance, which finally can lead to the impairment of erectile responses.

Hayward and coworkers [120] have shown that a mouse model that overexpresses human tumor necrosis factor alpha (hTNF-α) not only exhibits decreased induced erections but also decreased mounting behavior and number of intromissions. Conversely, TNF-α KO mice demonstrate increased number of spontaneous erections [118]. Additionally, isolated corpora cavernosa from TNF-α-infused mice display decreased NANC-dependent relaxation and increased sympathetic-mediated contractions in vitro (Figure 4), which would favor penile detumescence to occur [49]. Increased direct adrenergic responses were also observed in cavernosal tissue from TNF-α-infused mice [49]. Although TNF-α increases Ca²⁺ sensitivity in airway smooth muscle cell, the exact role on cavernosal smooth muscle remains speculative (Figure 4). Downregulation of eNOS and nNOS seems to be the mechanism underlying the functional changes in cavernosal strips from TNF-α-infused mice [49].

Figure 4.

Molecular mechanisms activated by tumor necrosis factor-alpha (TNF-α) which causes hypercontractility of cavernosal smooth muscle cells. Norepinephrine release from sympathethic nerve terminals activates α-adrenergic receptors that lead to the subsequent activation of specific G proteins and phospholipase C (PLC), which causes a rise in the concentration of cytoplasmic Ca²⁺. Increased intracellular Ca²⁺ then activates myosin light chain (MLC) and triggers smooth muscle contraction and subsequent penile flaccidity. Activation of Ras homolog gene family member A (RhoA) which is facilitated by guanosine nucleotide exchange factors (GEFs), stimulates downstream effectors, such as Rho-kinase. Activated Rho-kinase phosphorylates the regulatory subunit of myosin light chain phosphatase and inhibits its activity, thus facilitating smooth muscle cells contraction and flaccidity. TNF-α increases sympathetic- and α-adrenergic agonist-mediated contractions in corpora cavernosa and activates the RhoA/Rho-kinase signaling pathway.

It is interesting to note that the penile vasculature may not be only a target of widespread inflammation generated elsewhere, but it may actively participate in the whole process. Accordingly, the human corpus cavernosum has a local renin-angiotensin system (RAS) [121] and Ang II, one of the final products and the main known mediator of the RAS, which induces vascular injury through several mechanisms, including vasoconstriction, cell growth, oxidative stress production, and inflammation [122]. Similarly, the penile smooth muscle cells not only respond to but also synthesize endothelin-1 (ET-1), its converting enzyme (ECE-1), and both ET_A and ET_B receptor subtypes [123]. ET-1 not only induces vasoconstriction, but it also stimulates the expression of adhesion molecules and activates transcriptional factors responsible for the coordinated increase in the expression of many cytokines and enzymes, which can in turn lead to the production of inflammatory mediators [124,125]. Both peptides have been shown to increase TNF-α levels and this pro-inflammatory cytokine also positively regulates release of these vasoactive peptides [126-129]. More importantly, TNF-α inhibition slows the progression of hypertension and renal damage Ang II salt-sensitive hypertension [130] as well as in mineralocorticoid hypertension [131], a model where ET-1 plays a major role in end-organ damage [124,125,132,133]. In deoxycorticosterone-acetate (DOCA)-salt hypertensive animals, blockade of TNF-α actions with etanercept treatment reduces most indexes of renal inflammation independent of any blood pressure-lowering effect. In DOCA-salt hypertensive rats, TNF-α inhibition reduces monocyte chemoattractant protein-1 excretion and lowers renal cortical NF-kB activity. Urinary ET-1 excretion also decreases in DOCA-salt hypertensive rats on etanercept treatment along with reductions in renal cortical ICAM-1 expression [131].

It is noteworthy that diseases associated with high levels of TNF-α such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, and chronic obstructive pulmonary disease also have been associated with ED in males and, in many cases, with sexual dysfunction in females [117,134-138]. Although these evidence indicate that TNF-α may be the causal agent of ED, TNF-α is not alone in the list of cytokines, and a myriad of effects must coexist in all of these conditions.

Further studies are essential to determine whether TNF-α plays a detrimental role in ED associated with CVD such as hypertension, diabetes, CAD, and heart failure. Finally, a key role for TNF-α in mediating smooth muscle and endothelial dysfunction is of interest not only because markedly elevated serum levels of TNF-α have been documented in patients with ED, but also because we now have access to targeted anti-TNF-α therapies.