TNF-alpha knockout mice have increased corpora cavernosa relaxation.
BACKGROUND
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-alpha), a pro-inflammatory cytokine, suppresses endothelial nitric oxide synthase (eNOS) expression.


OBJECTIVE
Considering that nitric oxide (NO) is of critical importance in penile erection, we hypothesized that blockade of TNF-alpha actions would increase cavernosal smooth muscle relaxation.


METHODS
In vitro organ bath studies were used to measure cavernosal reactivity in wild type and TNF-alpha knockout (TNF-alpha 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.


METHODS
Corpora cavernosa from TNF-alpha KO mice exhibited increased NO-dependent relaxation, which was associated with increased eNOS and neuronal NOS (nNOS) cavernosal expression.


RESULTS
Cavernosal strips from TNF-alpha KO mice displayed increased endothelium-dependent (97.4 +/- 5.3 vs.


METHODS
76.3 +/- 6.3, %) and nonadrenergic-noncholinergic (93.3 +/- 3.0 vs.


METHODS
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.


METHODS
1.22 +/- 0.22; 16 Hz) as well as phenylephrine-induced contractile responses (1.6 +/- 0.1 vs.


METHODS
2.5 +/- 0.1, mN) were attenuated in cavernosal strips from TNF-alpha KO mice. Additionally, corpora cavernosa from TNF-alpha KO mice displayed increased collagen and elastin expression. In vivo experiments demonstrated that TNF-alpha KO mice display increased number of spontaneous erections.


CONCLUSIONS
Corpora cavernosa from TNF-alpha KO mice display alterations that favor penile tumescence, indicating that TNF-alpha plays a detrimental role in erectile function. A key role for TNF-alpha in mediating endothelial dysfunction in ED is markedly relevant since we now have access to anti-TNF-alpha therapies.
Carneiro
Fernando S
FS
Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo; Sao Paulo, SP, Brazil. fcarneiro@mcg.edu
Sturgis
Lashon C
LC
Giachini
Fernanda R C
FR
Carneiro
Zidonia N
ZN
Lima
Victor V
VV
Wynne
Brandi M
BM
San Martin
Sebastian
S
Brands
Michael W
MW
Tostes
Rita C
RC
Webb
R Clinton
RC
D000818:Animals; D003094:Collagen / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007172:Erectile Dysfunction / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010413:Penis; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D014664:Vasodilation / Q000502:physiology*
D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D004549:Elastin; D019001:Nitric Oxide Synthase