Ji Kan Ryu; Seung Min Oh; Hai Rong Jin Kang; Moon Song; Mi Hye Kwon; Do Kyung Kim; Jun Kyu Suh

doi:10.5534/kja.2012.30.1.23

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Ryu, Oh, Kang, Song, Kwon, Kim, and Suh: Transforming Growth Factor- β Type I Receptor Inhibitor Induces Functional and Morphologic Recovery in a Rat Model of Erectile Dysfunction and Cavernous Fibrosis

Original Article

Korean J Androl 2012;30(1):23-30.

Published online: 17 April 2012

DOI: https://doi.org/10.5534/kja.2012.30.1.23

Transforming Growth Factor- β Type I Receptor Inhibitor Induces Functional and Morphologic Recovery in a Rat Model of Erectile Dysfunction and Cavernous Fibrosis

Ji Kan Ryu, Seung Min Oh, Hai Rong Jin Kang, Moon Song, Mi Hye Kwon, Do Kyung Kim, Jun Kyu Suh

Department of Urology and National Research Center for Sexual Medicine, Inha University School of Medicine, Incheon, Korea

Correspondence to: Jun Kyu Suh Department of Urology and National Research Center for Sexual Medicine, Inha University School of Medicine, 7-206, 3rd ST, Shinheung-dong, Jung-gu, Incheon 400-711, Korea Tel: 032-890-3441, Fax: 032-890-3097 E-mail: jksuh@inha.ac.kr

^∗ Supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs (Jun-Kyu Suh, A110076), Korea.

Revised 26 January 20124 March 2012 Accepted 7 March 2012

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

To examine the effectiveness of small-molecule inhibitor of transforming growth factor-β (TGF-β) type I receptor, an activin receptor-like kinase 5 (ALK5), on erectile dysfunction (ED) in a rat model of cavernous fibrosis, in which fibrosis was induced by intracavernous injection of adenovirus expressing TGF-β1 (Ad-TGF-β1).

Conclusions

The results suggest that inhibition of the TGF-β pathway is a promising therapeutic strategy for the treatment of ED related to cavernous fibrosis from various causes.

Materials and Methods

Four-month-old Sprague-Dawley rats were divided into four groups (n=10 per group): age-matched controls without treatment, age-matched controls receiving intracavernous injection of LacZ adenovirus, and cavernous fibrosis rats receiving an intracavernous injection of saline or ALK5 inhibitor (5 mg/kg). ALK5 inhibitor or saline was administered on day 5 after injection of Ad-TGF-β1. On day 30, erectile function was assessed by electrical stimulation of the cavernous nerve and the penis was then harvested for histologic studies (n=6 per group) and for the measurement of the hydroxyproline level (n=4 per group).

Results

Ad-TGF-β1-induced cavernous fibrosis rats treated with saline showed a significant decrease in cavernous smooth muscle and endothelial content, and an increase in collagen deposition, which resulted in profound deterioration of all erectile function parameters, such as the ratios of maximal intracavernous pressure (ICP), total ICP, and slope to mean arterial pressure. ALK5 inhibitor significantly restored erectile function in a rat model of cavernous fibrosis by increasing cavernous smooth muscle and endothelial content, and by blocking cavernous fibrosis.

Keywords: Erectile dysfunction, Fibrosis, Transforming growth factor beta, TGF-beta type I receptor

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Fig. 1.

Activin receptor-like kinase 5 (ALK5) inhibitor restores intracavernous pressure (ICP) elicited by electrical stimulation of the cavernous nerve in an adenovirus expressing TGF-β1 (Ad-TGF-β1)-induced cavernous fibrosis model. (A) Representative ICP responses for the untreated control, LacZ adenovirus (Ad-LacZ)-treated control, and cavernous fibrosis model receiving intracavernous injection of saline or ALK5 inhibitor. (B∼D) Ratios of the mean maximal ICP, total ICP (area under the curve), and slope to mean arterial pressure (MAP) were calculated for each group. Each bar depicts the mean±standard deviations from n=6 animals per group. ∗p＜0.01 compared with other groups. ALK5I, small-molecule inhibitor of activin-like receptor kinase 5.

Fig. 2.

Activin receptor-like kinase 5 (ALK5) inhibitor promotes the regression of cavernous fibrosis and reduces collagen content in an adenovirus expressing TGF-β1 (Ad-TGF-β1)-induced cavernous fibrosis model. (A) Masson's trichrome staining of cavernous tissue from the untreated control, LacZ adenovirus (Ad-LacZ)-treated control, and cavernous fibrosis model receiving intracavernous injection of saline or ALK5 inhibitor. Magnification, 100×. (B) Cavernous hydroxyproline content in each group. Each bar depicts the mean±standard deviations from n=4 animals per group. ∗p＜0.05 compared with other groups. ALK5I, small-molecule inhibitor of activin-like receptor kinase 5.

Fig. 3.

Activin receptor-like kinase 5 (ALK5) inhibitor restores cavernous smooth muscle content in an adenovirus expressing TGF-β1 (Ad-TGF-β1)-induced cavernous fibrosis model. (A) Anti-smooth muscle α-actin staining of cavernous tissue from the untreated control, LacZ adenovirus (Ad-LacZ)-treated control, and cavernous fibrosis model receiving intracavernous injection of saline or ALK5 inhibitor. Magnification, 100×. (B) Quantitative analysis of smooth muscle cell content in cavernous tissue was performed using an image analyzer. Each bar depicts the mean±standard deviations from n=6 animals per group. ∗p＜0.01 compared with other groups. ALK5I, small-molecule inhibitor of activin-like receptor kinase 5.

Fig. 4.

Activin receptor-like kinase 5 (ALK5) inhibitor restores cavernous endothelial content in an adenovirus expressing TGF-β1 (Ad-TGF-β1)- induced cavernous fibrosis model. (A) Anti-factor VIII staining of cavernous tissue from the untreated control, LacZ adenovirus (Ad-LacZ)-treated control, and cavernous fibrosis model receiving intracavernous injection of saline or ALK5 inhibitor. Each figure was merged with factor VIII staining and phase image. Magnification, 200×. (B) Quantitative analysis of endothelial cell content in cavernous tissue was performed by using an image analyzer. Each bar depicts the mean±standard deviations from n=6 animals per group. ∗p＜0.01 compared with other groups. ALK5I, small-molecule inhibitor of activin-like receptor kinase 5.

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