Inhibition of proNGF and p75<SUP>NTR</SUP> Pathway Restores Erectile Function Through Dual Angiogenic and Neurotrophic Effects in the Diabetic Mouse

초록

Introduction: Penile neurovascular dysfunction is a major cause of erectile dysfunction (ED) in diabetic patients, which causes poor response to oral phosphodiesterase-5 inhibitors. Nerve growth factor precursor (proNGF) and its p75 neurotrophin receptor (p75(NTR)) have been known to be involved in microvascular complications and neurodegeneration. Aim: To examine the role of proNGF and its receptor p75(NTR) signaling pathway in diabetic ED, and to determine the effectiveness of proNGF neutralizing antibody (proNGF-Ab) in restoring erectile function in streptozotocin (STZ)-induced diabetic mice. Methods: Diabetes mellitus was induced by intraperitoneal injection of STZ (50 mg/kg) into 8-week-old C57BL/6 male mice for 5 consecutive days. At 8 weeks after the induction of diabetes mellitus, the animals were distributed into 3 groups: controls and STZ-induced diabetic mice receiving 2 intracavernous injections of either saline (days -3 and 0; 20 mu L) or proNGF-Ab (days -3 and 0; 20 mu g in 20 mu L of saline). We also examined the effect of proNGF-Ab or p75(NTR) small interfering RNA in primary cultured mouse cavernous endothelial cells, pericytes, and major pelvic ganglion. Main Outcome Measures: Erectile function was measured by electrical stimulation of the cavernous nerve at 2 weeks after treatment, and the penis was then harvested for histologic and biochemical studies. Results: The cavernous expression of proNGF and p75(NTR) was upregulated under diabetic conditions. Intracavernous injection of proNGF-Ab successfully restored erectile function in diabetic mice, which reach 93-96% of control values. ProNGF-Ab significantly restored cavernous endothelial cell, pericyte, and neuronal cell content, and increased endothelial cell-to-cell junction proteins in the diabetic mice. Under the high-glucose condition, proNGF-Ab or p75(NTR) small interfering RNA promoted tube formation in mouse cavernous endothelial cells and pericytes, decreased apoptosis of endothelial cells and pericytes, and enhanced neurite sprouting from major pelvic ganglion. Clinical Implications: The ProNGF/p75(NTR) pathway will be a new therapeutic target for diabetic ED. Strength & Limitations: This is the first study demonstrating the efficacy of the inhibition of proNGF/p75(NTR) pathway in diabetic ED. Further studies are needed to test whether a different dosing of proNGF-Ab would induce more durable erectile function recovery. Conclusion: Our findings suggest that inhibition of the proNGF/p75(NTR) signaling pathway is a promising therapeutic strategy for diabetic ED. Copyright (C) 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

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