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Erectile dysfunction 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.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.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 minutes). Collagen and elastin expression were evaluated by Masson trichrome and Verhoff-van Gieson stain reaction, respectively.Corpora cavernosa from TNF-α KO mice exhibited increased NO-dependent relaxation, which was associated with increased eNOS and neuronal NOS (nNOS) cavernosal expression.Cavernosal strips from TNF-α KO mice displayed increased endothelium-dependent (97.4 ± 5.3 vs. Control: 76.3 ± 6.3, %) and nonadrenergic-noncholinergic (93.3 ± 3.0 vs. Control: 67.5 ± 16.0; 16 Hz) relaxation compared to control animals. These responses were associated with increased protein expression of eNOS and nNOS (P < 0.05). Sympathetic-mediated (0.69 ± 0.16 vs. Control: 1.22 ± 0.22; 16 Hz) as well as phenylephrine-induced contractile responses (1.6 ± 0.1 vs. Control: 2.5 ± 0.1, mN) were attenuated in cavernosal strips from TNF-α KO mice. Additionally, corpora cavernosa from TNF-α KO mice displayed increased collagen and elastin expression. In vivo experiments demonstrated that TNF-α KO mice display increased number of spontaneous erections.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.