title: Restoration of erectile function by suppression of corporal apoptosis, fibrosis and corporal veno-occlusive dysfunction with rho-kinase inhibitors in a rat model of cavernous nerve injury.
abstract: OBJECTIVE
  We determined whether Rho-kinase inhibition would improve corporal veno-occlusive dysfunction by suppressing apoptosis and fibrosis via normalization of the Rho-kinase driven pathways related to the 2 structural alterations in a rat model of cavernous nerve crush injury.
  
  
  METHODS
  A total of 30 male 10-week-old male Sprague Dawley® rats were equally divided into 3 groups, including sham surgery, cavernous nerve crush injury and cavernous nerve crush injury treated with fasudil. The treated group received fasudil (30 mg/kg) daily for 4 weeks starting day 1 postoperatively. Electrostimulation and dynamic infusion cavernosometry were performed 4 weeks postoperatively. Penile tissue was processed for imm unohistochemistry, double immunofluorescent and Masson trichrome staining, TUNEL, caspase-3 activity assay and Western blot.
  
  
  RESULTS
  The cavernous nerve crush injury group showed significantly lower intracavernous pressure/mean arterial pressure, and higher maintenance and drop rates than the sham surgery group. Rho-kinase inhibition in the injury plus fasudil group restored erectile responses and dynamic infusion cavernosometry parameters. Increased apoptosis, decreased immunohistochemical staining of α-SMA and increased caspase-3 activity were noted in the injury group. In that group densitometry revealed increased ROCK1 expression, increased MYPT1 phosphorylation, decreased Akt phosphorylation, decreased Bad phosphorylation and a decreased Bcl2-to-Bax ratio. A significantly decreased smooth muscle-to-collagen ratio and increased fibroblast pCofilin were also observed in the injury group, as was increased phosphorylation of cofilin, a downstream effector of LIMK2. Rho-kinase inhibition in the injury plus fasudil group alleviated the histological and molecular dysregulation.
  
  
  CONCLUSIONS
  Our data suggest that early inhibition of Rho-kinase after cavernous nerve crush injury may prevent corporal apoptosis and fibrosis by suppressing the Akt/Bad/Bax/caspase-3 and LIMK2/cofilin pathways, preventing corporal veno-occlusive dysfunction and erectile dysfunction.
authors.affiliation: Department of Urology, Dongguk University College of Medicine, Goyang, Republic of Korea.
authors.forename: Min Chul
authors.initials: MC
authors.lastname: Cho
authors.affiliation: Department of Urology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Kwanjin
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Urology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Soo Woong
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Department of Urology, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: jspaick@snu.ac.kr.
authors.forename: Jae-Seung
authors.initials: JS
authors.lastname: Paick
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy; D008297:Male; D010410:Penile Erection; D010413:Penis / Q000098:blood supply / Q000293:injuries* / Q000294:innervation* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D014652:Vascular Diseases / Q000188:drug therapy*; D014680:Veins; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D054460:rho-Associated Kinases
keywords: erectile dysfunction; injury; nerves; penis; rho-associated kinases