title: Effectiveness of intracavernous delivery of adenovirus encoding Smad7 gene on erectile function in a mouse model of cavernous nerve injury.
abstract: BACKGROUND
  Men with erectile dysfunction (ED) respond poorly to oral phosphodiesterase-5 inhibitors following radical prostatectomy. Recent studies have reported that up-regulation of transforming growth factor-β1 (TGF-β1) and activation of the Smad signaling pathway play important roles in cavernous fibrosis and in the deterioration of erectile function in a mouse model of cavernous nerve injury (CNI) and in patients with spinal cord injury. The mothers against decapentaplegic homolog 7 (Smad7) is known to inhibit the phosphorylation of Smad2 and Smad3.
  
  
  OBJECTIVE
  To investigate the effectiveness of adenoviruses encoding Smad7 gene (Ad-Smad7) on erectile function in a mouse model of CNI.
  
  
  METHODS
  Twelve-week-old C57BL/6J mice were used and distributed into 7 groups: sham operation group, untreated CNI group, and CNI groups receiving a single intracavernous injection of adenovirus encoding LacZ (1 × 10(8) virus particles [vp]/20 μL) or adenovirus encoding Smad7 (Ad-Smad7; 1 × 10(7), 1 × 10(8), 2 × 10(8), or 1 × 10(9) vp/20 μL).
  
  
  METHODS
  Two weeks after bilateral cavernous nerve crushing and treatment, erectile function was measured by electrical stimulation of the cavernous nerve. The penis was harvested for histologic examinations and Western blot analysis.
  
  
  RESULTS
  The highest erectile response was noted in CNI mice treated with Ad-Smad7 at a dose of 1 × 10(8)  vp, which reached up to 82-85% of sham control values. Local delivery of Ad-Smad7 significantly decreased endothelial cell apoptosis and the production of extracellular matrix proteins, including plasminogen activator inhibitor-1, fibronectin, collagen I, and collagen IV, and induced endothelial nitric oxide synthase phosphorylation in the corpus cavernosum tissue of CNI mice.
  
  
  CONCLUSIONS
  The adenovirus-mediated gene transfer of Smad7 successfully restored erectile function by enhancing endothelial cell function and through antifibrotic effects. These findings suggest that inhibition of the TGF-β signaling pathway by use of Smad7 may represent a promising therapeutic strategy for ED induced by radical prostatectomy.
authors.affiliation: National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea.
authors.forename: Kang Moon
authors.initials: KM
authors.lastname: Song
authors.forename: Jae-Seung
authors.initials: JS
authors.lastname: Chung
authors.forename: Min Ji
authors.initials: MJ
authors.lastname: Choi
authors.forename: Hai-Rong
authors.initials: HR
authors.lastname: Jin
authors.forename: Guo Nan
authors.initials: GN
authors.lastname: Yin
authors.forename: Mi-Hye
authors.initials: MH
authors.lastname: Kwon
authors.forename: Jin-Mi
authors.initials: JM
authors.lastname: Park
authors.forename: Woo Jean
authors.initials: WJ
authors.lastname: Kim
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Ji-Kan
authors.initials: JK
authors.lastname: Ryu
authors.forename: Jun-Kyu
authors.initials: JK
authors.lastname: Suh
mesh_terms: D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D007172:Erectile Dysfunction / Q000209:etiology / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009409:Nerve Crush; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010410:Penile Erection; D010413:Penis / Q000294:innervation / Q000473:pathology / Q000601:surgery; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000628:therapy*; D010766:Phosphorylation; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D053773:Transforming Growth Factor beta1; D052250:Nitric Oxide Synthase Type III
keywords: Cavernous Fibrosis; Cavernous Nerve Injury; Endothelial Dysfunction; Erectile Dysfunction; Radical Prostatectomy; Smad7; Transforming Growth Factor Beta