Intracavernous Delivery of Freshly Isolated Stromal Vascular Fraction Rescues Erectile Function by Enhancing Endothelial Regeneration in the Streptozotocin-Induced Diabetic Mouse

Authors

  • 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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  • Munkhbayar Tumurbaatar MD,

    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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  • 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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  • Mi-Hye Kwon BS,

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

    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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  • 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 BS,

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

    1. National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon, Korea
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  • Young Jun Koh PhD,

    1. Department of Biological Sciences and Laboratory for Vascular Biology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
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  • Gou Young Koh MD, PhD,

    1. Department of Biological Sciences and Laboratory for Vascular Biology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 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
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  • Ji-Kan Ryu and Munkhbayar Tumurbaatar contributed equally to this study.

Jun-Kyu Suh, MD, PhD, National Research Center for Sexual Medicine and Department of Urology, Inha University School of Medicine, Incheon 400-711, Korea. Tel: 82-32-890-3441; Fax: 82-32-890-3097; E-mail: jksuh@inha.ac.kr

ABSTRACT

Introduction.  Men with diabetic erectile dysfunction (ED) often have severe endothelial dysfunction and respond poorly to oral phosphodiesterase-5 inhibitors.

Aim.  To examine whether and how freshly isolated stromal vascular fraction (SVF) promotes cavernous endothelial regeneration and restores erectile function in diabetic animals.

Methods.  Eight-week-old C57BL/6J mice were used. Diabetes was induced by intraperitoneal injection of streptozotocin. SVF was isolated from epididymal adipose tissues of green fluorescence protein transgenic mice. At 8 weeks after the induction of diabetes, the animals were divided into six groups: controls, diabetic mice, and diabetic mice treated with a single intracavernous injection of phosphate-buffered saline (PBS) or SVF (1 × 104 cells, 1 × 105 cells, or 2 × 105 cells/20 µL, respectively).

Main Outcome Measures.  Two weeks later, erectile function was measured by cavernous nerve stimulation. The penis was stained with antibodies to CD31, CD34, phosphohistone H3, phospho-endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor-A (VEGF-A). We also performed Western blot for phospho-eNOS and eNOS, and determined cyclic guanosine monophosphate (cGMP) concentration in the corpus cavernosum tissue.

Results.  Significant improvement in erectile function was noted in diabetic mice treated with SVF at concentrations of 1 × 105 and 2 × 105 cells, which reached up to 82% of the control values. Local delivery of SVF significantly increased cavernous endothelial cell proliferation, eNOS phosphorylation, and cGMP expression compared with that in the untreated group and the PBS-treated diabetic group. Intracavernous injection of SVF increased cavernous VEGF-A expression and induced recruitment of CD34(+)CD31(−) progenitor cells. Some SVF underwent differentiation into cavernous endothelial cells. SVF-induced promotion of cavernous angiogenesis and erectile function was abolished in the presence of VEGF-Trap, a soluble VEGF-A neutralizing antibody.

Conclusion.  The results support the concept of cavernous endothelial regeneration by use of SVF as a curative therapy for diabetic ED. Ryu J-K, Tumurbaatar M, Jin H-R, Kim WJ, Kwon M-H, Piao S, Choi MJ, Yin GN, Song K-M, Kang Y-J, Koh YJ, Koh GY, and Suh J-K. Intracavernous delivery of freshly isolated stromal vascular fraction rescues erectile function by enhancing endothelial regeneration in the streptozotocin-induced diabetic mouse. J Sex Med 2012;9:3051–3065.

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