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.
Highlights
Despite technical refinements in nerve-sparing radical prostatectomy, a significant proportion of men still suffer from erectile dysfunction (ED) as a major complication of RP [1,2,3,4,5,6]
We showed that the RhoA/ROCK1/LIM-kinase 2 (LIMK2)/Cofilin pathway contributed to cavernosal fibrosis with a loss of smooth muscle (SM) after cavernosal nerve (CN) injuries [17, 18]
This study demonstrated that chronic treatment with LIMK2 inhibitors alleviated cavernosal fibrosis through normalization of the LIMK2/Cofilin pathway, thereby resulting in improvement of cavernosal veno-occlusive dysfunction (CVOD), the main pathophysiologic mechanism of post-RP ED
Summary
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 [1,2,3,4,5,6]. 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 [7,8,9,10]. Several previous studies have reported that activated RhoA/ROCK1 or ROCK2 pathway plays a critical role in the development or progression of vascular fibrosis in cardiovascular diseases [12,13,14,15,16] In this context, we showed that the RhoA/ROCK1/LIM-kinase 2 (LIMK2)/Cofilin pathway contributed to cavernosal fibrosis with a loss of smooth muscle (SM) after CN injuries [17, 18]. Inhibiting a downstream pathway of ROCK such as LIMK2/Cofilin might be better than targeting ROCK itself in terms of both efficacy and safety [21]
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