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Expression of the Apelin–APJ Pathway and Effects on Erectile Function in a Mouse Model of Vasculogenic Erectile Dysfunction

Authors

  • Mi-Hye Kwon MS,

    1. National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
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    • Mi-Hye Kwon and Buyankhuu Tuvshintur contributed equally to this study.
  • Buyankhuu Tuvshintur MS,

    1. National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
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    • Mi-Hye Kwon and Buyankhuu Tuvshintur contributed equally to this study.
  • Woo Jean Kim PhD,

    1. National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
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  • Hai-Rong Jin MD, PhD,

    1. National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
    2. Department of Urology, Yuhuangding Hospital, Yantai, Shandong Province, China
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  • Guo Nan Yin PhD,

    1. National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
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  • Kang-Moon Song MS,

    1. National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
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  • Min Ji Choi MS,

    1. National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
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  • Ki-Dong Kwon BS,

    1. National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
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  • Dulguun Batbold BS,

    1. National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
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  • Ji-Kan Ryu MD, PhD,

    1. National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
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  • Jun-Kyu Suh MD, PhD

    Corresponding author
    1. National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
    • Corresponding Authors: Jun-Kyu Suh, MD, PhD, National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, 7-206, 3rd ST, Shinheung-Dong, Jung-Gu, Incheon 400-711, Republic of Korea. Tel: 82-32-890-3441; Fax: 82-32-890-3097; E-mail: jksuh@inha.ac.kr; Ji-Kan Ryu, MD, PhD, National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, 7-206, 3rd ST, Shinheung-Dong, Jung-Gu, Incheon 400-711, Republic of Korea. Tel: 82-32-890-3505; Fax: 82-32-890-3099, E-mail: rjk0929@inha.ac.kr

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Abstract

Introduction

Much attention has recently been focused on therapeutic angiogenesis as a treatment for erectile dysfunction (ED). The apelin and apelin receptor (APJ) system is known to cause endothelium-dependent vasodilatation and to be involved in angiogenesis.

Aim

To examine the differential expression of apelin and APJ in animal models of vasculogenic ED and to determine whether and how enhancement of apelin–APJ signaling restores erectile function in hypercholesterolemic mice.

Methods

Acute cavernous ischemia was induced in C57BL/6J mice by bilateral occlusion of internal iliac arteries, and chronic vasculogenic ED was induced by feeding a high-cholesterol diet or by intraperitoneal injection of streptozotocin.

Main Outcome Measures

Messenger RNA (mRNA) levels of apelin and APJ were determined in cavernous tissue of each vasculogenic ED model by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). We evaluated erectile function by electrical stimulation of the cavernous nerve in hypercholesterolemic mice 1, 3, 7, and 14 days after a single intracavernous injection of apelin protein (5 μg/20 μL). The penis was harvested for histologic examinations and Western blot analysis.

Results

The cavernous mRNA expression of apelin and APJ was up-regulated in acute ischemia model and down-regulated in chronic vasculogenic ED models. A significant restoration of erectile function was noted 1 day after injection of apelin protein into the penis of hypercholesterolemic mice; however, erectile function returned to baseline values thereafter. The beneficial effects of apelin on erectile function resulted mainly from an activation of endothelial nitric oxide synthase and increase in nitric oxide bioavailability through reduction in reactive oxygen species-mediated endothelial apoptosis rather than through direct endothelial cell proliferation.

Conclusion

These findings suggest that apelin–APJ signaling is a potential therapeutic target in the treatment of vasculogenic ED. Further studies are needed to develop a potent agonist for APJ and to determine the role of repeated dosing of apelin on long-term recovery of erectile function. Kwon M-H, Tuvshintur B, Kim WJ, Jin H-R, Yin GN, Song K-M, Choi MJ, Kwon K-D, Batbold D, Ryu J-K, and Suh J-K. Expression of the apelin–APJ pathway and effects on erectile function in a mouse model of vasculogenic erectile dysfunction. J Sex Med 2013;10:2928–2941.

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