TNF-α Knockout Mice Have Increased Corpora Cavernosa Relaxation

Abstract

Introduction-Erectile dysfunction (ED) is considered an early clinical manifestation of vascular disease and an independent risk factor for cardiovascular events associated with endothelial dysfunction and increased levels of pro-inflammatory cytokines. Tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine, suppresses endothelial nitric oxide synthase (eNOS) expression.Aim-Considering that nitric oxide (NO) is of critical importance in penile erection, we hypothesized that blockade of TNF-α actions would increase cavernosal smooth muscle relaxation through an increase in NOS expression.Methods-In vitro organ bath studies were used to measure cavernosal reactivity in wild type and TNF-α knockout (TNF-α KO) mice and NOS expression was evaluated by western blot. In addition, spontaneous erections (in vivo) were evaluated by videomonitoring the animals (30 min.). Collagen and elastin expression were evaluated by Masson trichrome and Verhoff-van Gieson stain reaction, respectively.Main Outcome Measures-Corpora cavernosa from TNF-α KO mice exhibited increased NOdependent relaxation, which was associated with increased eNOS and neuronal NOS (nNOS) cavernosal expression. Conclusion-Corpora cavernosa from TNF-α KO mice display alterations that favor penile tumescence, indicating that TNF-α plays a detrimental role in erectile function. A key role for TNF-α in mediating endothelial dysfunction in ED is markedly relevant since we now have access to anti-TNF-α therapies. Results-Cavernosal Keywordstumor necrosis factor alpha; corpus cavernosum; endothelial nitric oxide synthase; neuronal nitric oxide synthase; mouse INTRODUCTIONErectile dysfunction (ED), defined as the consistent inability to achieve and maintain penile erection sufficient for adequate sexual relations, is a prevalent condition affecting more than 150 million men worldwide. ED, which is considered the early clinical manifestation of generalized vascular disease and an independent risk factor for cardiovascular events, is NIH Public Access

Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: An experimental study in the rabbit

“…Transgenic animals overexpressing TNFa showed erectile dysfunction (Hayward et al, 2007). Conversely, TNFa knockout mice exhibited enhanced penile NO-dependent relaxation, as well as increased eNOS expression (Carneiro et al, 2009). These findings suggest that TNFa directly induces an endothelial injury in different vascular beds.…”

Mechanisms of Penile Erection and Basis for Pharmacological Treatment of Erectile Dysfunction

“…TNF-␣ KO mice were found to exhibit changes in cavernosal reactivity that would facilitate erectile responses. Thus the animals showed decreased responses to adrenergic nerve stimulation and increased NANC-and endothelium-dependent relaxation that were associated with increased corporal eNOS and nNOS protein levels (Carneiro et al, 2009). TNF-␣ impaired endothelium-dependent and NOmediated vasodilation in various vascular beds (Chen et al, 2008;Zhang et al, 2009a), and a key role for TNF-␣ in mediating endothelial dysfunction in ED has been suggested (Carneiro et al, 2009).…”

“…Thus the animals showed decreased responses to adrenergic nerve stimulation and increased NANC-and endothelium-dependent relaxation that were associated with increased corporal eNOS and nNOS protein levels (Carneiro et al, 2009). TNF-␣ impaired endothelium-dependent and NOmediated vasodilation in various vascular beds (Chen et al, 2008;Zhang et al, 2009a), and a key role for TNF-␣ in mediating endothelial dysfunction in ED has been suggested (Carneiro et al, 2009). Blockade of TNF-␣ actions (which is clinically possible) may theoretically represent an alternative therapeutic approach for erectile dysfunction, especially in pathological conditions associated with increased levels of this cytokine.…”

Animal models of erectile dysfunction (ED): potential utility of non-human primates as a model of atherosclerosis-induced vascular ED

“…For example, knockout mice have been used to study the role of tumor necrosis factor-a in corpora cavernosa relaxation. 80 Adenosine actions on ED have been explored in obese and type 2 diabetic db/db mouse 81 as well as in A2B receptor-knockout mice. 82 Mouse models of NO pathway disruption have been critical in defining the role of vasodilators as targets for the treatment of ED.…”