Research Article: Chronic administration of LIMK2 inhibitors alleviates cavernosal veno-occlusive dysfunction through suppression of cavernosal fibrosis in a rat model of erectile dysfunction after cavernosal nerve injury

Date Published: March 14, 2019

Publisher: Public Library of Science

Author(s): Juhyun Park, Hwancheol Son, Ji Sun Chai, Soo Woong Kim, Jae-Seung Paick, Min Chul Cho, Vinayak Shenoy.

http://doi.org/10.1371/journal.pone.0213586

Abstract

We evaluated whether chronic administration of LIMK2-inhibitors could improve erectile function by alleviating CVOD through suppressing cavernosal fibrosis in a rat model of cavernosal nerve crush-injury (CNCI). Forty-two 12-week-old rats were equally categorized into the 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 30-days after surgery. Erectile function was assessed using dynamic-infusion-cavernosometry (DIC). Penile tissue was processed for Masson’s-trichrome staining, Western-blotting, and double immunofluorescence. 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 those in the I-group, although the parameters were not completely restored to normal control values. Also, the I-group showed a reduced smooth muscle (SM)-to-collagen ratio, decreased immunohistochemical staining for α-SM-actin, increased number of fibroblasts positive for phosphorylated Cofilin, increased LIMK2/Cofilin phosphorylation and increased protein expression of Collagen-1 or Fibronectin, compared to the S-group. The L-group showed significant improvements in SM/collagen ratio and the deposition of Collagen-1 or Fibronectin compared to the I-group, although not completely normalized. According to the densitometry and confocal microscopy results, the L-group showed restoration of LIMK2/Cofilin phosphorylation and amount of fibroblasts positive for phosphorylated Cofilin to the normal control value. In conclusion, chronic inhibition of LIMK2 can improve CVOD and ED by alleviating cavernosal fibrosis via normalizing the LIMK2/Cofilin pathway.

Partial Text

Despite technical refinements in nerve-sparing radical prostatectomy (ns-RP), a significant proportion of men still suffer from erectile dysfunction (ED) as a major complication of RP [1–6]. Even when surgically meticulous techniques are applied to avoid direct damage to the cavernosal nerve (CN), ED can occur as a consequence of neuropraxia caused by traction, compression, coagulation and minimal manipulation [4, 7]. The neuropraxia induces loss of nocturnal penile tumescence, and subsequently, low oxygen supply to the penis during the early postoperative period [7]. This penile hypoxia leads to irreversible structural changes such as cavernosal apoptosis and fibrosis, thereby resulting in cavernosal veno-occlusive dysfunction (CVOD), which is known as the key pathophysiology of post-RP ED [7–10].

Damage to CNs during RP is a factor that causes postoperative cavernosal fibrosis [4, 7, 8]. Cavernosal fibrosis with loss of SM induced by CN injuries predisposes to the development of CVOD after RP [7, 24]. Thus, alleviation of CVOD through suppression of cavernosal fibrosis can be a meaningful strategy for improving post-RP ED. According to our recent study using LIMK2 inhibitors, the LIMK2/Cofilin pathway may play a critical role in the development of cavernosal fibrosis caused by CNCI, suggesting a therapeutic strategy targeting the LIMK2/Cofilin pathway for alleviation of cavernosal fibrosis and post-RP ED [22]. In this context, the present study was designed to identify the beneficial effect of chronic treatment with LIMK2 inhibitors on CVOD caused by CNCI. This study demonstrated that chronic treatment with LIMK2 inhibitors alleviated cavernosal fibrosis through normalization of the LIMK2/Cofilin pathway, thereby resulting in improvement of CVOD, the main pathophysiologic mechanism of post-RP ED.

On the basis of our data, chronic inhibition of LIMK2 may alleviate CVOD, and thereby post-RP ED by improving cavernosal fibrosis via normalizing the LIMK2/Cofilin pathway, although the recovery is incomplete. Thus, interventions targeting the LIMK2/Cofilin pathway, at least as a part of combination therapies, may be reasonable therapeutic options for alleviation of cavernosal fibrosis and CVOD induced by CN injury, leading to maximization of the chance of improvement in post-RP ED. In the future, further investigations are necessary to validate this therapeutic strategy.

 

Source:

http://doi.org/10.1371/journal.pone.0213586

 

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