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DICKKOPF2 PROMOTES ANGIOGENESIS AND NEURAL REGENERATION THROUGH AN ANGIOPOIETIN-1-TIE2 PATHWAY AND RESCUES ERECTILE FUNCTION IN THE DIABETIC MOUSE

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Sources of Funding: This study was supported by MW (Ji-Kan Ryu, HI15C0508) and MRC (Jun-Kyu Suh, 2014R1A5A2009392) funded by MSIP, Republic of Korea.

Introduction

Introduction and Objective: Men with diabetic erectile dysfunction (ED) often have severe endothelial dysfunction and peripheral nerve damage, which result in poor response to oral phosphodiesterase-5 inhibitors. Dickkopf2 (DKK2), originally known as Wnt antagonists, is known to enhance neovascularization in animal models of both hind limb ischemia and myocardial infarction. The aim of this study was to investigate the mechanisms through which DKK2 restores diabetes-induced ED.

Methods

Methods: Four groups of mice were used: wild type (WT) mice, DKK2-Tg mice, WT mice receiving streptozotocin (STZ), and DKK2-Tg mice receiving STZ. Eight weeks after the induction of diabetes, we measured erectile function by electrical stimulation of the cavernous nerve. We also determined efficacy of DKK2 protein in STZ-injected WT diabetic mice 2 weeks after repeated intracavernous injections of DKK2 protein (days -3 and 0; 6 µg/20 µl). The penis was stained with antibodies to CD31, smooth muscle ?-actin, NG2, PDGFR-?, claudin-5, VE-cadherin, eNOS, phospho-eNOS, oxidized LDL, nNOS, ?III tubulin, and neurofilament. We also performed Western blot for DKK2, Ang1, Ang2, NGF, BDNF, NT-3, and TrkA in the corpus cavernosum tissue.

Results

Results: Overexpression of DKK2 by using DKK2-Tg mice or by administering DKK2 protein successfully restored erectile function through enhanced penile angiogenesis and neural regeneration. DKK2 decreased extravasation of oxidized-LDL by restoring pericyte content and endothelial cell-cell junction proteins. Ang1 expression was down-regulated and Ang2 expression was up-regulated in the diabetic penis compared with that in controls, and these changes were reversed by DKK2 treatment. DKK2-mediated penile angiogenesis and neural regeneration as well as erectile function recovery was abolished by inhibition of Ang1-Tie2 signaling with soluble Tie2 antibody or Ang1 siRNA.

Conclusions

Conclusions: The dual angiogenic and neurotrophic effects of DKK2, especially local therapy in the form of therapeutic protein, will open a new avenue to treat diabetic ED.

Funding

This study was supported by MW (Ji-Kan Ryu, HI15C0508) and MRC (Jun-Kyu Suh, 2014R1A5A2009392) funded by MSIP, Republic of Korea.

Authors
GUO NAN YIN
Hai-Rong Jin
Jiyeon Ock
Min Ji Choi
Kang-Moon Song
Anita Limanjaya
Kalyan Ghatak
Nguyen Nhat Minh
Soo-Hwan Park
Ji-Kan Ryu
Jun-Kyu Suh
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