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 journalArticle

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

Fingerprint

Angiopoietin-1
Pericytes
Erectile Dysfunction
Regeneration
Endothelial Cells
Angiopoietin-2
Penile Erection
Phosphodiesterase 5 Inhibitors
Gene Expression Profiling
Neurites
Coculture Techniques
Cell Communication
Nervous System
Blood Vessels
Proteins
Genes
Therapeutics

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Yin, G. N., Jin, H. R., Choi, M. J., Limanjaya, A., Ghatak, K., Minh, N. N., ... 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
Yin, Guo Nan ; Jin, Hai Rong ; Choi, Min Ji ; Limanjaya, Anita ; Ghatak, Kalyan ; Minh, Nguyen Nhat ; Ock, Jiyeon ; Kwon, Mi Hye ; Song, Kang Moon ; Park, Heon Joo ; Kim, Ho Min ; Kwon, Young-Guen ; Ryu, Ji Kan ; Suh, Jun Kyu. / Pericyte-Derived Dickkopf2 regenerates damaged penile neurovasculature through an angiopoietin-1-Tie2 pathway. In: Diabetes. 2018 ; Vol. 67, No. 6. pp. 1149-1161.
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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.",
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Yin, GN, Jin, HR, Choi, MJ, Limanjaya, A, Ghatak, K, Minh, NN, Ock, J, Kwon, MH, Song, KM, Park, HJ, Kim, HM, Kwon, Y-G, Ryu, JK & Suh, JK 2018, 'Pericyte-Derived Dickkopf2 regenerates damaged penile neurovasculature through an angiopoietin-1-Tie2 pathway', Diabetes, vol. 67, no. 6, pp. 1149-1161. https://doi.org/10.2337/db17-0833

Pericyte-Derived Dickkopf2 regenerates damaged penile neurovasculature through an angiopoietin-1-Tie2 pathway. / Yin, Guo Nan; Jin, Hai Rong; Choi, Min Ji; Limanjaya, Anita; Ghatak, Kalyan; Minh, Nguyen Nhat; Ock, Jiyeon; Kwon, Mi Hye; Song, Kang Moon; Park, Heon Joo; Kim, Ho Min; Kwon, Young-Guen; Ryu, Ji Kan; Suh, Jun Kyu.

In: Diabetes, Vol. 67, No. 6, 01.06.2018, p. 1149-1161.

Research output: Contribution to journalArticle

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T1 - Pericyte-Derived Dickkopf2 regenerates damaged penile neurovasculature through an angiopoietin-1-Tie2 pathway

AU - Yin, Guo Nan

AU - Jin, Hai Rong

AU - Choi, Min Ji

AU - Limanjaya, Anita

AU - Ghatak, Kalyan

AU - Minh, Nguyen Nhat

AU - Ock, Jiyeon

AU - Kwon, Mi Hye

AU - Song, Kang Moon

AU - Park, Heon Joo

AU - Kim, Ho Min

AU - Kwon, Young-Guen

AU - Ryu, Ji Kan

AU - Suh, Jun Kyu

PY - 2018/6/1

Y1 - 2018/6/1

N2 - 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.

AB - 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.

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