Dickkopf2 rescues erectile function by enhancing penile neurovascular regeneration in a mouse model of cavernous nerve injury

Kalyan Ghatak, Guo Nan Yin, Min Ji Choi, Anita Limanjaya, Nguyen Nhat Minh, Jiyeon Ock, Kang Moon Song, Dong Hyuk Kang, Young-Guen Kwon, Ho Min Kim, Ji Kan Ryu, Jun Kyu Suh

Research output: Contribution to journalArticle

Abstract

Penile erection is a neurovascular event and neurologic or vascular disturbances are major causes of erectile dysfunction (ED). Radical prostatectomy for prostate cancer not only induces cavernous nerve injury (CNI) but also results in cavernous angiopathy, which is responsible for poor responsiveness to oral phosphodiesterase-5 inhibitors. Dickkopf2 (DKK2) is known as a Wnt signaling antagonist and is reported to promote mature and stable blood vessel formation. Here, we demonstrated in CNI mice that overexpression of DKK2 by administering DKK2 protein or by using DKK2-Tg mice successfully restored erectile function: this recovery was accompanied by enhanced neural regeneration through the secretion of neurotrophic factors, and restoration of cavernous endothelial cell and pericyte content. DKK2 protein also promoted neurite outgrowth in an ex vivo major pelvic ganglion culture experiment and enhanced tube formation in primary cultured mouse cavernous endothelial cells and pericytes co-culture system in vitro. In light of critical role of neuropathy and angiopathy in the pathogenesis of radical prostatectomy-induced ED, reprogramming of damaged erectile tissue toward neurovascular repair by use of a DKK2 therapeutic protein may represent viable treatment option for this condition.

Original languageEnglish
Article number17819
JournalScientific reports
Volume7
Issue number1
DOIs
Publication statusPublished - 2017 Dec 1

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Regeneration
Pericytes
Erectile Dysfunction
Prostatectomy
Blood Vessels
Wounds and Injuries
Endothelial Cells
Penile Erection
Phosphodiesterase 5 Inhibitors
Proteins
Recovery of Function
Nerve Growth Factors
Coculture Techniques
Ganglia
Nervous System
Prostatic Neoplasms
Therapeutics
Neuronal Outgrowth
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • General

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Ghatak, Kalyan ; Yin, Guo Nan ; Choi, Min Ji ; Limanjaya, Anita ; Minh, Nguyen Nhat ; Ock, Jiyeon ; Song, Kang Moon ; Kang, Dong Hyuk ; Kwon, Young-Guen ; Kim, Ho Min ; Ryu, Ji Kan ; Suh, Jun Kyu. / Dickkopf2 rescues erectile function by enhancing penile neurovascular regeneration in a mouse model of cavernous nerve injury. In: Scientific reports. 2017 ; Vol. 7, No. 1.
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abstract = "Penile erection is a neurovascular event and neurologic or vascular disturbances are major causes of erectile dysfunction (ED). Radical prostatectomy for prostate cancer not only induces cavernous nerve injury (CNI) but also results in cavernous angiopathy, which is responsible for poor responsiveness to oral phosphodiesterase-5 inhibitors. Dickkopf2 (DKK2) is known as a Wnt signaling antagonist and is reported to promote mature and stable blood vessel formation. Here, we demonstrated in CNI mice that overexpression of DKK2 by administering DKK2 protein or by using DKK2-Tg mice successfully restored erectile function: this recovery was accompanied by enhanced neural regeneration through the secretion of neurotrophic factors, and restoration of cavernous endothelial cell and pericyte content. DKK2 protein also promoted neurite outgrowth in an ex vivo major pelvic ganglion culture experiment and enhanced tube formation in primary cultured mouse cavernous endothelial cells and pericytes co-culture system in vitro. In light of critical role of neuropathy and angiopathy in the pathogenesis of radical prostatectomy-induced ED, reprogramming of damaged erectile tissue toward neurovascular repair by use of a DKK2 therapeutic protein may represent viable treatment option for this condition.",
author = "Kalyan Ghatak and Yin, {Guo Nan} and Choi, {Min Ji} and Anita Limanjaya and Minh, {Nguyen Nhat} and Jiyeon Ock and Song, {Kang Moon} and Kang, {Dong Hyuk} and Young-Guen Kwon and Kim, {Ho Min} and Ryu, {Ji Kan} and Suh, {Jun Kyu}",
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Ghatak, K, Yin, GN, Choi, MJ, Limanjaya, A, Minh, NN, Ock, J, Song, KM, Kang, DH, Kwon, Y-G, Kim, HM, Ryu, JK & Suh, JK 2017, 'Dickkopf2 rescues erectile function by enhancing penile neurovascular regeneration in a mouse model of cavernous nerve injury', Scientific reports, vol. 7, no. 1, 17819. https://doi.org/10.1038/s41598-017-17862-5

Dickkopf2 rescues erectile function by enhancing penile neurovascular regeneration in a mouse model of cavernous nerve injury. / Ghatak, Kalyan; Yin, Guo Nan; Choi, Min Ji; Limanjaya, Anita; Minh, Nguyen Nhat; Ock, Jiyeon; Song, Kang Moon; Kang, Dong Hyuk; Kwon, Young-Guen; Kim, Ho Min; Ryu, Ji Kan; Suh, Jun Kyu.

In: Scientific reports, Vol. 7, No. 1, 17819, 01.12.2017.

Research output: Contribution to journalArticle

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AU - Ghatak, Kalyan

AU - Yin, Guo Nan

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AU - Limanjaya, Anita

AU - Minh, Nguyen Nhat

AU - Ock, Jiyeon

AU - Song, Kang Moon

AU - Kang, Dong Hyuk

AU - Kwon, Young-Guen

AU - Kim, Ho Min

AU - Ryu, Ji Kan

AU - Suh, Jun Kyu

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Y1 - 2017/12/1

N2 - Penile erection is a neurovascular event and neurologic or vascular disturbances are major causes of erectile dysfunction (ED). Radical prostatectomy for prostate cancer not only induces cavernous nerve injury (CNI) but also results in cavernous angiopathy, which is responsible for poor responsiveness to oral phosphodiesterase-5 inhibitors. Dickkopf2 (DKK2) is known as a Wnt signaling antagonist and is reported to promote mature and stable blood vessel formation. Here, we demonstrated in CNI mice that overexpression of DKK2 by administering DKK2 protein or by using DKK2-Tg mice successfully restored erectile function: this recovery was accompanied by enhanced neural regeneration through the secretion of neurotrophic factors, and restoration of cavernous endothelial cell and pericyte content. DKK2 protein also promoted neurite outgrowth in an ex vivo major pelvic ganglion culture experiment and enhanced tube formation in primary cultured mouse cavernous endothelial cells and pericytes co-culture system in vitro. In light of critical role of neuropathy and angiopathy in the pathogenesis of radical prostatectomy-induced ED, reprogramming of damaged erectile tissue toward neurovascular repair by use of a DKK2 therapeutic protein may represent viable treatment option for this condition.

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