Ruan Y, Zhou J, Kang N, Reed-Maldonado AB, Tamaddon A, Wang B, Wang HS, Wang G, Banie L, Lin G, Liu J, Lue TF.
Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.
Department of Urology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.

Abstract

OBJECTIVES: To investigate the feasibility of Zucker fatty rats as a model for obesity-associated erectile dysfunction (OAED) research and to determine the effect of low intensity extracorporeal shock wave therapy (Li-ESWT) on penile tissue and function in these rats.
MATERIALS AND METHODS: Eight newborn male Zucker Lean (ZL group) rats (ZUC-Leprfa 186) and 16 newborn male Zucker Fatty (ZF) rats (ZUC-Leprfa 185) were injected with 5-ethynyl-2'-deoxyuridine (EdU) at birth to identify and monitor endogenous stem cells. Insulin tolerance testing was performed at 10 weeks of age. Beginning at 12 weeks of age, 8 ZF rats were kept as controls, and the remaining 8 ZF rats were treated with Li-ESWT (0.02 mJ/mm2 , 3 Hz, 500 pulses; ZF + SW group) twice a week for 4 weeks. Following a 1-week washout period, erectile function was evaluated by measuring intracavernosal pressure (ICP) and mean arterial pressure (MAP). Penile tissues were then harvested for histological study to assess smooth muscle/collagen content and endothelium content in the corpora cavernosum. LipidTOX staining was used to evaluate lipid accumulation. EdU as a marker of cell activation and phosphorylated histone 3 (H3P) as a marker of cell mitosis were also assessed.
RESULTS: The ICP/MAP indicated that erectile function was severely impaired in the ZF group as compared with the ZL group. In the ZF + Li-SW group, erectile function was significantly improved (P<0.05). Muscle atrophy was observed in the ZF group while Li-ESWT increased the muscle content in ZF + SW group. Moreover, the penile endothelium was damaged in the ZF group, and Li-ESWT enhanced the regeneration of endothelial cells (P<0.01) in the ZF + SW group. Lipid accumulation was observed in the penile tissue of ZF rats. Li-ESWT significantly reduced both the amount and the distribution pattern of LipidTOX suggesting decreased overall lipid infiltration. Furthermore, Li-ESWT increased EdU+ cells and markedly enhanced the phosphorylation level of H3P at Ser-10 in the ZF + SW group. Most H3P positive cells were located within smooth muscle cells with some located in the endothelium suggesting that these tissues are the reservoirs of penile stem/progenitor cells.
CONCLUSION: ZF rats can serve as an animal model in which to study OAED. This study reveals that obesity impairs erectile function by causing smooth muscle atrophy, endothelial dysfunction, and lipid accumulation in the corpus cavernosum. Li-ESWT restored penile hemodynamic parameters in the ZF rats by restoring smooth muscle and endothelium content and reducing lipid accumulation. The underlying mechanism of Li-ESWT appears to be activation of stem/progenitor cells which prompts cellular proliferation and accelerates penile tissue regeneration. Our findings are of interest not just as a validation of this emerging treatment for erectile dysfunction but also as a novel and potentially significant method to modulate endogenous stem/progenitor cells in other disease processes. This article is protected by copyright. All rights reserved.

BJU Int. 2018 Mar 23. doi: 10.1111/bju.14202. [Epub ahead of print]