Pericyte-Derived Dickkopf2 regenerates damaged penile neurovasculature through an angiopoietin-1-Tie2 pathway

Guo Nan Yin, Hai Rong Jin, Min Ji Choi, Anita Limanjaya, Kalyan Ghatak, Nguyen Nhat Minh, Jiyeon Ock, Mi Hye Kwon, Kang Moon Song, Heon Joo Park, Ho Min Kim, Young Guen Kwon, Ji Kan Ryu, Jun Kyu Suh

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4 Citations (Scopus)

Abstract

Penile erection requires well-coordinated interactions between vascular and nervous systems. Penile neurovascular dysfunction is a major 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 coculture 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.

Original languageEnglish
Pages (from-to)1149-1161
Number of pages13
JournalDiabetes
Volume67
Issue number6
DOIs
Publication statusPublished - 2018 Jun 1

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Yin, G. N., Jin, H. R., Choi, M. J., Limanjaya, A., Ghatak, K., Minh, N. N., Ock, J., Kwon, M. H., Song, K. M., Park, H. J., Kim, H. M., Kwon, Y. G., Ryu, J. K., & Suh, J. K. (2018). Pericyte-Derived Dickkopf2 regenerates damaged penile neurovasculature through an angiopoietin-1-Tie2 pathway. Diabetes, 67(6), 1149-1161. https://doi.org/10.2337/db17-0833