Derangements in Endothelial Cell-to-Cell Junctions Involved in the Pathogenesis of Hypercholesterolemia-Induced Erectile Dysfunction

Authors

  • Ji-Kan Ryu MD, PhD,

    1. Department of Urology and National Research Laboratory of Regenerative Sexual Medicine, Inha University School of Medicine, Incheon, Korea;
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  • Lu Wei Zhang MD, PhD,

    1. Department of Urology and National Research Laboratory of Regenerative Sexual Medicine, Inha University School of Medicine, Incheon, Korea;
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  • Hai-Rong Jin MD,

    1. Department of Urology and National Research Laboratory of Regenerative Sexual Medicine, Inha University School of Medicine, Incheon, Korea;
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  • Shuguang Piao MD, PhD,

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

    1. Department of Urology and National Research Laboratory of Regenerative Sexual Medicine, Inha University School of Medicine, Incheon, Korea;
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  • Buyankhuu Tuvshintur BS,

    1. Department of Urology and National Research Laboratory of Regenerative Sexual Medicine, Inha University School of Medicine, Incheon, Korea;
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  • Munkhbayar Tumurbaatar MD,

    1. Department of Urology and National Research Laboratory of Regenerative Sexual Medicine, Inha University School of Medicine, Incheon, Korea;
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  • Sun Hwa Shin BS,

    1. Department of Urology and National Research Laboratory of Regenerative Sexual Medicine, Inha University School of Medicine, Incheon, Korea;
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  • Jee-Young Han MD, PhD,

    1. Department of Pathology, Inha University School of Medicine, Incheon, Korea
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  • Woo Jean Kim PhD,

    Corresponding author
    1. Department of Urology and National Research Laboratory of Regenerative Sexual Medicine, Inha University School of Medicine, Incheon, Korea;
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  • Jun-Kyu Suh MD, PhD

    Corresponding author
    1. Department of Urology and National Research Laboratory of Regenerative Sexual Medicine, Inha University School of Medicine, Incheon, Korea;
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  • Ji-Kan Ryu and Lu Wei Zhang contributed equally to this study.

Jun-Kyu Suh, MD, PhD, Department of Urology and Laboratory of Regenerative Sexual Medicine, Inha University School of Medicine, 7-206, 3rd Street, Shinheung-Dong, Jung-Gu, Incheon 400-711, Korea. Tel: 82-32-890-3441; Fax: 82-32-890-3097; E-mail: jksuh@inha.ac.kr

Woo Jean Kim, PhD, Department of Urology and Laboratory of Regenerative Sexual Medicine, Inha University School of Medicine, 7-206, 3rd Street, Shinheung-Dong, Jung-Gu, Incheon 400-711, Korea. Tel: 82-32-890-2466; Fax: 82-32-890-2462; E-mail: pangjean@korea.com

ABSTRACT

Introduction.  Endothelial cell-to-cell junctions are crucial for vascular formation, networking, and remodeling of blood vessels as well as for inducing and integrating intracellular signals.

Aim.  We investigated the differential expression and distribution of endothelial cell-to-cell junction proteins in the penis of mice with hypercholesterolemia-induced erectile dysfunction.

Methods.  Two-month-old C57BL/6J mice were fed a diet containing 4% cholesterol and 1% cholic acid, and age-matched control animals were fed a normal diet, for 3 months. We performed dual priming oligonucleotide (DPO)-based multiplex polymerase chain reaction (PCR) (Seegene, Seoul, Korea) to screen the differential gene expression of 21 endothelial cell-to-cell junctions.

Main Outcome Measures.  At 5 months, erectile function was measured by electrical stimulation of the cavernous nerve, and the penis was harvested and stained with antibody to claudin-5, vascular endothelial (VE)-cadherin, and platelet/endothelial cell adhesion molecule (PECAM)-1 (N = 8 per group). Cavernous specimens from a separate group of animals were used for claudin-5, VE-cadherin, and PECAM-1 reverse transcriptase-PCR and Western blot analysis.

Results.  Erectile function was significantly lower in hypercholesterolemic mice than in controls. DPO-based multiplex PCR revealed a profound decrease in the gene expression of endothelium-specific cell-to-cell junction proteins, including claudin-5, VE-cadherin, and PECAM-1, in hypercholesterolemic mice compared with that in controls. The expression of claudin-5, VE-cadherin, and PECAM-1 protein evaluated by Western blot or immunohistochemistry was significantly lower in hypercholesterolemic mice than in controls. These endothelial cell-to-cell junction proteins were more sparsely distributed in the endothelium of cavernous sinusoids than in the endothelium of cavernous artery and dorsal blood vessels.

Conclusion.  Down-regulation of the endothelial cell-to-cell junctions and decreased endothelial content in the corpus cavernosum might play a major role in the deterioration of erectile function in hypercholesterolemic mice. Ryu J-K, Zhang LW, Jin H-R, Piao S, Choi MJ, Tuvshintur B, Tumurbaatar M, Shin SH, Han J-Y, Kim WJ, and Suh J-K. Derangements in endothelial cell-to-cell junctions involved in the pathogenesis of hypercholesterolemia-induced erectile dysfunction. J Sex Med 2009;6:1893–1907.

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