Introduction

Cavernosal fibrosis is a key pathophysiology of post-RP ED. Previously, we showed that ROCK1/LIMK2/Cofilin pathway could play a role in cavernosal fibrosis and ED in a rat model of cavernosal nerve (CN) injury. Also, our recent study noted that short-term administration of LIMK2 inhibitors (10.0 mg/kg) alleviated cavernosal fibrosis induced by CN injury. The aim of this study was to determine whether chronic adminstration of LIMK2 inhibitors could improve erectile function by alleviating cavernosal veno-occlusive dysfunction (CVOD) via suppressing cavernosal fibrosis in a rat model of CN injury.

Methods

Forty-two 11-week-old rats were equally randomized into three groups: sham surgery (S), CNCI (I), and CNCI treated with LIMK2 inhibitors (L). The L group was treated with daily intraperitoneal injection of LIMK2 inhibitors (10.0 mg/kg) for 4 weeks from the following day after surgery. The S and I groups were treated with daily intraperitoneal administration of saline vehicle only. At 4 weeks after surgery, erectile function was assessed using dynamic infusion cavernosometry (DIC). Penile tissue was processed for Masson’s trichrome staining, immunohistochemical staining to alpha-smooth muscle actin (?-SMA), Western blot, and double immunofluorescence with antibody to Vimentin and phosphorylated Cofilin.

Results

There was no signi?cant difference in body weight change and mean arterial pressue among the 3 groups. The I group showed significantly higher maintenance and drop rates as well as lower papaverine response, compared to the S group. Chronic inhibition of LIMK2 in the L group significantly improved the DIC parameters compared to the I group, although they were not completely restored to normal control values. Also, the I group showed a reduced smooth muscle-to-collagen ratio, decreased immunohistochemical staining of ?-SMA, increased fibroblasts positive for phosphorylated Cofilin and increased Cofilin phosphorylation, compared to the S group. Chronic inhibition of LIMK2 in the L group significantly alleviated the histological and molecular dysregulation compared to the I group.

Conclusions

Our data indicate that chronic inhibition of LIMK2 can improve CVOD and ED by alleviating cavernosal fibrosis via normalizing LIMK2/Cofilin pathway. Thus, a new therapeutic strategy targeting the LIMK2/Cofilin pathway may be helpful to alleviate CVOD and ED through prevention of cavernosal fibrosis after CN injury.

Funding

none