Suppression of Cavernosal Fibrosis in a Rat Model

Introduction: Cavernosal fibrosis is an important pathologic condition leading to erectile dysfunction (ED). The etiologies of cavernosal fibrosis include aging, diabetes mellitus, castration, cavernosal nerve injury during radical prostatectomy, hypertension, and Peyronie disease. Aims: To summarize published studies investigating suppression of cavernosal fibrosis in rat models of ED of various etiologies. Methods: A literature search was conducted using PubMed. Relevant studies were identified using search terms such as erectile dysfunction, penis, fibrosis, and rat models. Main Outcome Measures: We reviewed representative literature studies on the mechanisms and suppression of cavernosal fibrosis in rat models of ED. Results: The underlying mechanisms and potential therapeutic strategies suggested thus far for cavernosal fibrosis in rat models of ED were as follows. For age-related ED involving oxidative stress and tumor growth factor-beta 1 (TGF-beta 1)edriven pathways such as RhoA-ROCK1-LIMK2-cofilin or p42-44 and mitogen-activated protein kinase, proposed therapeutic strategies included phosphodiesterase type 5 inhibitors (PDE5Is), kallikrein-kinin system stimulators, and calorie restriction. For diabetes-related ED involving angiotensin-II- and TGF-beta 1-driven Smad and non-Smad pathways, TGF-beta 1-Wnt10b, and histone deacetylase (HDAC)-TGF-beta 1 pathways, positive therapeutic results were obtained with PDE5Is, TGF-beta 1 antagonists, HDAC inhibitors, antioxidants, sphingosine-1-phosphate receptor modulators (fingolimod), angiotensin-II antagonists, stem cell therapy, and antidiabetic drugs. For cavernosal nerve injury-associated ED involving TGF-beta 1-driven pathways (Smad or RhoA-ROCK1-LIMK2-cofilin), Sonic hedgehog signaling, angiotensin-II-Smad, and HDAC4-TGF-beta 1-Smad signaling triggered by cavernosal hypoxia, PDE5Is, angiotensin-II antagonists, stem cell therapy, HDAC inhibitors, Sonic hedgehog administration, ROCK inhibitors, and LIMK2 inhibitors have shown positive results. For testosterone deficiency-associated ED, TGF-beta 1-driven pathways were found to be responsive to testosterone supplementation. For hypertensive ED, positive therapeutic results were obtained with angiotensin-II antagonists. For Peyronie disease involving TGF-beta 1 or myostatin signaling, proposed therapeutic strategies included intra-tunical injection of TGF-beta receptor inhibitors or adipose tissue-derived stem cells and HDAC2 small hairpin RNA. Conclusion: Several signaling pathways appear to be responsible for the development of cavernosal fibrosis related to ED of various etiologies. Some therapeutic success has been achieved in animal models, but further research focusing on mechanism-specific targeted therapies is needed. Copyright (C) 2018, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.