Journal
DIABETES
Volume 67, Issue 6, Pages 1149-1161Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db17-0833
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Funding
- Korean Health Technology RD Project
- Ministry of Health & Welfare, Republic of Korea [A110076, H15C0508]
- Medical Research Center [2014R1A5A2009392]
- National Research Foundation of Korea (NRF)
- Korean government (Ministry of Science, ICT and Future Planning) [2016R1A2B2010087]
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Penile erection requires well-coordinated interactions between vascular and nervous systems. Penile neurovascular dysfunction is amajor cause of erectile dysfunction (ED) in patients with diabetes, which causes poor response to oral phosphodiesterase-5 inhibitors. Dickkopf2 (DKK2), a Wnt antagonist, is known to promote angiogenesis. Here, using DKK2-Tg mice or DKK2 protein administration, we demonstrate that the overexpression of DKK2 in diabetic mice enhances penile angiogenesis and neural regeneration and restores erectile function. Transcriptome analysis revealed that angiopoietin-1 and angiopoietin-2 are target genes for DKK2. Using an endothelial cell-pericyte co-culture system and ex vivo neurite sprouting assay, we found that DKK2-mediated juxtacrine signaling in pericyte-endothelial cell interactions promotes angiogenesis and neural regeneration through an angiopoietin-1-Tie2 pathway, rescuing erectile function in diabetic mice. The dual angiogenic and neurotrophic effects of DKK2, especially as a therapeutic protein, will open new avenues to treating diabetic ED.
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