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

Research output: Contribution to journalArticlepeer-review

10 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

Bibliographical note

Funding Information:
Funding. This work was supported by a grant from the Korean Health Technology R&D Project; the Ministry of Health & Welfare, Republic of Korea (grants A110076 [to J.-K.S.] and H15C0508 [to J.-K.R. and H.M.K.]); a Medical Research Center Grant (grant 2014R1A5A2009392 [to J.-K.R. and H.J.P.]); and the National Research Foundation of Korea (NRF), funded by the Korean government (Ministry of Science, ICT and Future Planning, grant 2016R1A2B2010087 [to J.-K.R.]). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. G.N.Y. and H.-R.J. designed and performed the experiments and wrote the manuscript. M.-J.C., A.L., K.G., N.N.M., J.O., M.-H.K., and K.-M.S. performed the experiments. H.J.P. analyzed and critically discussed the data. H.M.K. and Y.-G.K. contributed essential reagents. J.-K.R. and J.-K.S. designed the experiments, supervised the project, and wrote the manuscript. J.-K.R. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding Information:
This work was supported by a grant from the Korean Health Technology R&D Project; the Ministry of Health & Welfare, Republic of Korea (grants A110076 [to J.-K.S.] and H15C0508 [to J.-K.R. and H.M.K.]); a Medical Research Center Grant (grant 2014R1A5A2009392 [to J.-K.R. and H.J.P.]); and the National Research Foundation of Korea (NRF), funded by the Korean government (Ministry of Science, ICT and Future Planning, grant 2016R1A2B2010087 [to J.-K.R.]).

Publisher Copyright:
© 2018 by the American Diabetes Association.

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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