Neuromedin B Restores Erectile Function by Protecting the Cavernous Body and the Nitrergic Nerves from Injury in a Diabetic Rat Model.

Hiroaki Nishimatsu,Etsu Suzuki,Daisuke Yamada,Yasuho Saito,Akira Nomiya,Aya Niimi,Yukio Homma,Michael Bader

doi:10.1371/journal.pone.0133874

Hiroaki Nishimatsu, Etsu Suzuki + Show 6 more

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https://doi.org/10.1371/journal.pone.0133874

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Abstract

Erectile dysfunction (ED) is a major health problem worldwide and affects approximately 75% of diabetic patients, likely due to severely damaged cavernous body. While screening for cytokines produced by adipose tissue-derived stem cells, we detected neuromedin B (NMB). To explore a potential treatment option for ED, we examined whether NMB was capable of restoring erectile function. We also examined the potential mechanism by which NMB could restore erectile function. Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. An adenovirus expressing NMB (AdNMB) was injected into the penis 6 weeks after STZ administration. Four weeks after the injection of AdNMB, erectile function, penile histology, and protein expression were analyzed. As assessed by the measurement of intracavernous pressure, AdNMB injection significantly restored erectile function compared with the injection of an adenovirus expressing green fluorescent protein. This restoration was associated with conservation of the cavernous body structure and neural nitric oxide synthase (nNOS)-expressing nerves, together with recovery of α-smooth muscle actin, vascular endothelial-cadherin, and nNOS expression. Furthermore, NMB significantly stimulated the survival of SH-SY5Y cells derived from human neuroblastoma tissue with characteristics similar to neurons. Collectively, these results suggested that NMB restored erectile function via protection of the cavernous body from injury and stimulation of the survival of the associated nerves. NMB may be useful to treat ED patients with a severely damaged cavernous body.

Highlights

Erectile dysfunction (ED) is a major health problem worldwide
HEK293 cells infected with adenovirus expressing NMB (AdNMB) produced significantly greater amounts of neuromedin B (NMB) protein than those infected with adenovirus that expressed green fluorescent protein (AdGFP) (Fig 2A), suggesting that the AdNMB used in this study produced NMB
The penises injected with AdNMB expressed significantly higher amounts of NMB mRNA than those injected with AdGFP (Fig 2B), suggesting that the AdNMB injected into the penises remained there and expressed NMB

Summary

Introduction

Erectile dysfunction (ED) is a major health problem worldwide. It is a common complication of diabetes in men, estimated to affect approximately 75% of these patients [1]. Among a variety of adult stem cells, bone marrow-derived mesenchymal stem cells (BMMSCs) and adipose tissue-derived stem cells (ASCs), which are derived from subcutaneous adipose tissue, have been widely used to treat ED in animal models [8, 10,11,12,13,14,15]. Both BMMSCs and ASCs are effective for the treatment of ED, the mechanisms by which they restore erectile function remain controversial. Among the various cytokines produced by ASCs, we identified adrenomedullin (AM) and angiopoietin-1 (Ang-1) as molecules that effectively protected the cavernous body from injury [17]

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