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

• Published in: Scientific reports Vol. 7; no. 1; pp. 17819 - 11
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.12.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/2; 14/1; 14/19; 631/378/1804; 631/378/368; 64/60; 82/51; Androgens; Animals; Axonogenesis; Blood Vessels - drug effects; Blood Vessels - metabolism; Cancer surgery; Cell culture; Coculture Techniques - methods; Disease Models, Animal; Dkk2 protein; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium - drug effects; Endothelium - metabolism; Erectile dysfunction; Erectile Dysfunction - drug therapy; Erectile Dysfunction - metabolism; Ganglion Cysts - drug therapy; Ganglion Cysts - metabolism; Humanities and Social Sciences; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; multidisciplinary; Nerve Growth Factors - metabolism; Nerve Regeneration - drug effects; Neurites - drug effects; Neurites - metabolism; Neuropathy; Neurotrophic factors; Pelvis; Penile Erection - drug effects; Penis; Penis - drug effects; Penis - metabolism; Pericytes; Pericytes - drug effects; Pericytes - metabolism; Phosphodiesterase; Phosphodiesterase 5 Inhibitors - pharmacology; Prostate cancer; Prostatectomy; Prostatectomy - adverse effects; Proteins; Regeneration; Rodents; Science; Science (multidisciplinary); Secretion; Trauma, Nervous System - drug therapy; Urological surgery; Wnt protein
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-17862-5

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.