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Low\u2010intensity pulsed ultrasound (LIPUS) can be a potential strategy for neurogenic ED (NED). However, whether Schwann cells (SCs) can respond to LIPUS stimulation signals is unclear. This study aims to elucidate the signal transmission between SCs paracrine exosome (Exo) and neurons stimulated by LIPUS, as well as to analyze the role and potential mechanisms of exosomes in CN repair after injury.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The major pelvic ganglion (MPG) neurons and MPG\/CN explants were stimulated with LIPUS of different energy intensities to explore the appropriate LIPUS energy intensity. The exosomes were isolated and purified from LIPUS\u2010stimulated SCs (LIPUS\u2010SCs\u2010Exo) and non\u2010stimulated SCs (SCs\u2010Exo). The effects of LIPUS\u2010SCs\u2010Exo on neurite outgrowth, erectile function, and cavernous penis histology were identified in bilateral cavernous nerve crush injury (BCNI)\u2010induced ED rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>LIPUS\u2010SCs\u2010Exo group can enhance the axon elongation of MPG\/CN and MPG neurons compared to SCs\u2010Exo group in vitro. Then, the LIPUS\u2010SCs\u2010Exo group showed a stronger ability to promote the injured CN regeneration and SCs proliferation compared to the SCs\u2010Exo group in vivo. Furthermore, the LIPUS\u2010SCs\u2010Exo group increased the Max intracavernous pressure (ICP)\/mean arterial pressure (MAP), lumen to parenchyma and smooth muscle to collagen ratios compared to the SCs\u2010Exo group in vivo. Additionally, high\u2010throughput sequencing combined with bioinformatics analysis revealed the differential expression of 1689 miRNAs between the SCs\u2010Exo group and the LIPUS\u2010SCs\u2010Exo group. After LIPUS\u2010SCs\u2010Exo treatment, the phosphorylated levels of Phosphatidylinositol 3\u2010kinase (PI3K), protein kinase B (Akt) and forkhead box O (FoxO) in MPG neurons increased significantly compared to negative control (NC) and SCs\u2010Exo groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study revealed that LIPUS stimulation could regulate the gene of MPG neurons by changing miRNAs derived from SCs\u2010Exo, then activating the PI3K\u2010Akt\u2010FoxO signal pathway to enhance nerve regeneration and restore erectile function. This study had important theoretical and practical significance for improving the NED treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.14256","type":"journal-article","created":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T05:49:36Z","timestamp":1683611376000},"page":"3239-3258","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["<scp>LIPUS\u2010SCs\u2010Exo<\/scp> promotes peripheral nerve regeneration in cavernous nerve crush injury\u2010induced <scp>ED<\/scp> rats via <scp>PI3K<\/scp>\/Akt\/<scp>FoxO<\/scp> signaling pathway"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5248-847X","authenticated-orcid":false,"given":"Kun","family":"Ye","sequence":"first","affiliation":[{"name":"Department of Urology The Fifth Affiliated Hospital of Sun Yat\u2010Sen University  Zhuhai Guangdong China"},{"name":"Guangdong Provincial Key Laboratory of Biomedical Imaging The Fifth 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