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低强度脉冲超声通过增强施万细胞介导的海绵体神经再生改善双侧海绵体神经损伤所致的勃起功能障碍。

Low-intensity pulsed ultrasound ameliorates erectile dysfunction induced by bilateral cavernous nerve injury through enhancing Schwann cell-mediated cavernous nerve regeneration.

机构信息

Department of Urology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China.

Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, China.

出版信息

Andrology. 2023 Sep;11(6):1188-1202. doi: 10.1111/andr.13406. Epub 2023 Feb 17.

Abstract

BACKGROUND

Cavernous nerve injury-induced erectile dysfunction caused by pelvic surgery or trauma is refractory to conventional medications and required an alternative treatment. Low-intensity pulsed ultrasound is a noninvasive mechanical therapy that promotes nerve regeneration.

OBJECTIVES

To investigate the therapeutic effect and potential mechanism of low-intensity pulsed ultrasound in the treatment of neurogenic erectile dysfunction.

MATERIALS AND METHODS

Thirty rats were randomly divided into the sham-operated group, bilateral cavernous nerve injury group, and bilateral cavernous nerve injury + low-intensity pulsed ultrasound group. The erectile function was assessed 3 weeks after daily low-intensity pulsed ultrasound treatment. The penile tissues and cavernous nerve tissues were harvested and subjected to histologic analysis. Primary Schwann cells and explants were extracted from adult rats. The effects of low-intensity pulsed ultrasound on proliferation, migration, and nerve growth factor expression of Schwann cells and axonal elongation were examined in vitro. RNA sequencing and western blot assay were applied to predict and verify the molecular mechanism of low-intensity pulsed ultrasound-induced Schwann cell activation.

RESULTS

Our study showed that low-intensity pulsed ultrasound promoted Schwann cells proliferation, migration, and neurotrophic factor nerve growth factor expression. Meanwhile, low-intensity pulsed ultrasound exhibits a stronger ability to enhance Schwann cells-mediated neurite outgrowth of major pelvic ganglion neurons and major pelvic ganglion/cavernous nerve explants in vitro. In vivo experiments demonstrated that the erectile function of the rats in the bilateral cavernous nerve injury + low-intensity pulsed ultrasound group was significantly higher than those in the bilateral cavernous nerve injury groups. Moreover, the expression levels of smooth muscle and cavernous endothelium also increased significantly in the bilateral cavernous nerve injury + low-intensity pulsed ultrasound group. In addition, we observed the higher density and number of cavernous nerve regenerating axons in the bilateral cavernous nerve injury + low-intensity pulsed ultrasound group, indicating that low-intensity pulsed ultrasound promotes axonal regeneration following cavernous nerve injury in vivo. RNA sequencing analysis and bioinformatic analysis suggested that low-intensity pulsed ultrasound might trigger the activation of the PI3K/Akt pathway. Western blot assay confirmed that low-intensity pulsed ultrasound activated Schwann cells through TrkB/Akt/CREB signaling.

CONCLUSIONS

Low-intensity pulsed ultrasound promoted nerve regeneration and ameliorated erectile function by enhancing Schwann cells proliferation, migration, and neurotrophic factor nerve growth factor expression. The TrkB/Akt/CREB axis is the possible mechanism of low-intensity pulsed ultrasound-mediated Schwann cell activation. Low-intensity pulsed ultrasound-based therapy could be a novel potential treatment strategy for cavernous nerve injury-induced neurogenic erectile dysfunction.

摘要

背景

骨盆手术或创伤引起的海绵体神经损伤导致的勃起功能障碍对常规药物治疗无反应,需要替代治疗。低强度脉冲超声是一种促进神经再生的非侵入性机械治疗方法。

目的

研究低强度脉冲超声治疗神经源性勃起功能障碍的疗效及潜在机制。

材料与方法

30 只大鼠随机分为假手术组、双侧海绵体神经损伤组和双侧海绵体神经损伤+低强度脉冲超声组。每日低强度脉冲超声治疗 3 周后评估阴茎勃起功能。采集阴茎组织和海绵体神经组织进行组织学分析。从成年大鼠中提取原代许旺细胞和组织外植体。在体外研究低强度脉冲超声对许旺细胞增殖、迁移和神经营养因子神经生长因子表达以及轴突伸长的影响。应用 RNA 测序和 Western blot 检测预测和验证低强度脉冲超声诱导许旺细胞激活的分子机制。

结果

本研究表明,低强度脉冲超声促进许旺细胞增殖、迁移和神经营养因子神经生长因子表达。同时,低强度脉冲超声在体外增强主要盆神经神经元和主要盆神经/海绵体神经外植体中许旺细胞介导的轴突伸长的能力更强。体内实验表明,双侧海绵体神经损伤+低强度脉冲超声组大鼠的勃起功能明显高于双侧海绵体神经损伤组。此外,双侧海绵体神经损伤+低强度脉冲超声组平滑肌和海绵体内皮的表达水平也显著增加。此外,我们观察到双侧海绵体神经损伤+低强度脉冲超声组海绵体神经再生轴突的密度和数量更高,表明低强度脉冲超声促进了海绵体神经损伤后的轴突再生。RNA 测序分析和生物信息学分析表明,低强度脉冲超声可能通过触发 PI3K/Akt 通路激活许旺细胞。Western blot 检测证实,低强度脉冲超声通过 TrkB/Akt/CREB 信号通路激活许旺细胞。

结论

低强度脉冲超声通过增强许旺细胞增殖、迁移和神经营养因子神经生长因子表达促进神经再生,改善勃起功能。TrkB/Akt/CREB 轴可能是低强度脉冲超声介导许旺细胞激活的潜在机制。基于低强度脉冲超声的治疗可能成为治疗海绵体神经损伤引起的神经源性勃起功能障碍的一种新的潜在治疗策略。

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