{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T09:13:28Z","timestamp":1788599608044,"version":"build-2803163510"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:p>\n                    Phenotypic modulation of corpus cavernosum smooth muscle cells (CCSMCs) is closely related to the occurrence of erectile dysfunction (ED). However, the effect of exosomes (EXOs) on the phenotypic modulation of CCSMCs with diabetes mellitus (DM)-related ED is not fully understood. Using a rat model of type 2 DM, we found an important role for phenotypic modulation of CCSMCs in DM-related ED. EXO secretion by CCSMCs is also driven by pathological changes to the corpus cavernosum in diabetic rats. We used CCSMCs subjected to platelet-derived growth factor-BB as an\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    model of phenotypic modulation and isolated EXOs from the supernatants of cultured CCSMCs by ultracentrifugation. The results suggest that phenotypic modulation enhances the capacity of CCSMCs to secrete EXOs and that inhibiting EXO secretion could restore the contractile phenotype of CCSMCs\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    . Notably, a further mechanistic study revealed that regulated EXO secretion could change the phenotype of CCSMCs via the neutral sphingomyelinase-2 (nSMase2) pathway. Taken together, our results indicate that the modulation of EXO biogenesis and secretion may be a novel therapeutic approach to improve type 2 DM-induced ED by maintaining the contractile phenotype of CCSMCs.\n                  <\/jats:p>","DOI":"10.4103\/aja202569","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T08:00:11Z","timestamp":1773820811000},"page":"516-525","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Phenotypic modulation of corpus cavernosum smooth muscle cells in type 2 diabetic rats is mediated by regulated exosomes secretion via neutral sphingomyelinase-2"],"prefix":"10.4103","volume":"28","author":[{"given":"Feng-Zhi","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Urology, Shenzhen Second People\u2019s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China"},{"name":"Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Shenzhen Second People\u2019s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Tao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, Shenzhen Second People\u2019s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China"},{"name":"Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Shenzhen Second People\u2019s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin-Yu","family":"Zeng","sequence":"additional","affiliation":[{"name":"Shenzhen Baoan Middle School (Group) The Second Foreign Language School, Shenzhen 518125, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing-Xin","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510510, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Bing","family":"Mei","sequence":"additional","affiliation":[{"name":"Department of Urology, Shenzhen Second People\u2019s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China"},{"name":"Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Shenzhen Second People\u2019s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen 518000, China"},{"name":"Department of Urology, Shenzhen Second People\u2019s Hospital, Clinical Medicine College of Anhui Medical University, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An-Yang","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510510, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"key":"R1-20260905","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.4252\/wjsc.v13.i10.1549","article-title":"Stem cell therapy and diabetic erectile dysfunction: a critical review","volume":"13","author":"Pakpahan","year":"2021","journal-title":"World J Stem Cells"},{"key":"R2-20260905","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.sxmr.2020.02.001","article-title":"Gene polymorphisms affecting erectile dysfunction","volume":"8","author":"Mostafa","year":"2020","journal-title":"Sex Med Rev"},{"key":"R3-20260905","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.jsxm.2021.01.175","article-title":"Caspase signaling in ED patients and animal models","volume":"18","author":"Martin","year":"2021","journal-title":"J Sex Med"},{"key":"R4-20260905","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.esxm.2019.10.003","article-title":"Testosterone induces relaxation of human corpus cavernosum tissue of patients with erectile dysfunction","volume":"8","author":"Van den Broeck","year":"2020","journal-title":"Sex Med"},{"key":"R5-20260905","doi-asserted-by":"crossref","first-page":"895044","DOI":"10.3389\/fphar.2022.895044","article-title":"Erectile dysfunction: key role of cavernous smooth muscle cells","volume":"13","author":"de Souza","year":"2022","journal-title":"Front Pharmacol"},{"key":"R6-20260905","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.niox.2020.11.003","article-title":"Administration of H2S improves erectile dysfunction by inhibiting phenotypic modulation of corpus cavernosum smooth muscle in bilateral cavernous nerve injury rats","volume":"107","author":"Zeng","year":"2021","journal-title":"Nitric Oxide"},{"key":"R7-20260905","doi-asserted-by":"crossref","first-page":"363","DOI":"10.5534\/wjmh.210226","article-title":"Myocardin reverses hypoxia-inducible factor-1 alpha mediated phenotypic modulation of corpus cavernosum smooth muscle cells in hypoxia induced by cobalt chloride","volume":"41","author":"Zhou","year":"2023","journal-title":"World J Mens Health"},{"key":"R8-20260905","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/ijir.2012.16","article-title":"Characterization of corpus cavernosum smooth muscle cell phenotype in diabetic rats with erectile dysfunction","volume":"24","author":"Wei","year":"2012","journal-title":"Int J Impot Res"},{"key":"R9-20260905","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.ncrna.2023.05.004","article-title":"Emerging functions and clinical applications of exosomal microRNAs in diseases","volume":"8","author":"Ghafouri-Fard","year":"2023","journal-title":"Noncoding RNA Res"},{"key":"R10-20260905","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s41232-023-00279-1","article-title":"Bone regeneration in inflammation with aging and cell-based immunomodulatory therapy","volume":"43","author":"Kushioka","year":"2023","journal-title":"Inflamm Regen"},{"key":"R11-20260905","doi-asserted-by":"crossref","first-page":"115715","DOI":"10.1016\/j.biopha.2023.115715","article-title":"Exosomes loaded with chondrogenic stimuli agents combined with 3D bioprinting hydrogel in the treatment of osteoarthritis and cartilage degeneration","volume":"168","author":"Zhang","year":"2023","journal-title":"Biomed Pharmacother"},{"key":"R12-20260905","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1007\/s12015-023-10594-2","article-title":"Host and pathogen-directed therapies against microbial infections using exosome- and antimicrobial peptide-derived stem cells with a special look at pulmonary infections and sepsis","volume":"19","author":"Moosazadeh Moghaddam","year":"2023","journal-title":"Stem Cell Rev Rep"},{"key":"R13-20260905","first-page":"206","article-title":"A multifunctional neuromodulation platform utilizing Schwann cell-derived exosomes orchestrates bone microenvironment via immunomodulation, angiogenesis and osteogenesis","volume":"23","author":"Hao","year":"2023","journal-title":"Bioact Mater"},{"key":"R14-20260905","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.jbior.2014.10.002","article-title":"Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes","volume":"57","author":"Shamseddine","year":"2015","journal-title":"Adv Biol Regul"},{"key":"R15-20260905","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1161\/CIRCRESAHA.116.305012","article-title":"Vascular smooth muscle cell calcification is mediated by regulated exosome secretion","volume":"116","author":"Kapustin","year":"2015","journal-title":"Circ Res"},{"key":"R16-20260905","doi-asserted-by":"crossref","first-page":"1435701","DOI":"10.3389\/fimmu.2024.1435701","article-title":"Dynamic changes in the proximitome of neutral sphingomyelinase-2 (nSMase2) in TNF\u03b1 stimulated Jurkat cells","volume":"15","author":"Schol","year":"2024","journal-title":"Front Immunol"},{"key":"R17-20260905","doi-asserted-by":"crossref","first-page":"H1344","DOI":"10.1152\/ajpheart.00222.2004","article-title":"Neutral sphingomyelinase inhibitor scyphostatin prevents and ceramide mimics mechanotransduction in vascular endothelium","volume":"287","author":"Czarny","year":"2004","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"R18-20260905","doi-asserted-by":"crossref","first-page":"3233","DOI":"10.1007\/s12035-022-02747-0","article-title":"Neutral sphingomyelinase 2 mediates oxidative stress effects on astrocyte senescence and synaptic plasticity transcripts","volume":"59","author":"Zhu","year":"2022","journal-title":"Mol Neurobiol"},{"key":"R19-20260905","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1159\/000336649","article-title":"Endothelin-1 stimulates small artery VCAM-1 expression through p38MAPK-dependent neutral sphingomyelinase","volume":"49","author":"Ohanian","year":"2012","journal-title":"J Vasc Res"},{"key":"R20-20260905","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1161\/ATVBAHA.118.311208","article-title":"nSMase2 (type 2-neutral sphingomyelinase) deficiency or inhibition by GW4869 reduces inflammation and atherosclerosis in Apoe-\/- mice","volume":"38","author":"Lallemand","year":"2018","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"R21-20260905","doi-asserted-by":"crossref","first-page":"9178","DOI":"10.3390\/ijms23169178","article-title":"Vascular smooth muscle cell neutral sphingomyelinase 2 in the release of exosomes and vascular calcification","volume":"23","author":"Pavlic","year":"2022","journal-title":"Int J Mol Sci"},{"key":"R22-20260905","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1016\/j.jsxm.2017.07.005","article-title":"Adipose-derived stem cell-derived exosomes ameliorate erectile dysfunction in a rat model of type 2 diabetes","volume":"14","author":"Chen","year":"2017","journal-title":"J Sex Med"},{"key":"R23-20260905","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1111\/andr.12375","article-title":"Maintenance of the contractile phenotype in corpus cavernosum smooth muscle cells by Myocardin gene therapy ameliorates erectile dysfunction in bilateral cavernous nerve injury rats","volume":"5","author":"Zhang","year":"2017","journal-title":"Andrology"},{"key":"R24-20260905","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/and.12261","article-title":"Myocardin restores erectile function in diabetic rats: phenotypic modulation of corpus cavernosum smooth muscle cells","volume":"47","author":"He","year":"2015","journal-title":"Andrologia"},{"key":"R25-20260905","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1152\/physrev.00041.2003","article-title":"Molecular regulation of vascular smooth muscle cell differentiation in development and disease","volume":"84","author":"Owens","year":"2004","journal-title":"Physiol Rev"},{"key":"R26-20260905","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1002\/cbic.201800470","article-title":"Exosomes: isolation, analysis, and applications in cancer detection and therapy","volume":"20","author":"Bu","year":"2019","journal-title":"Chembiochem"},{"key":"R27-20260905","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/s13287-023-03345-0","article-title":"Stem cell-derived exosomes: emerging therapeutic opportunities for wound healing","volume":"14","author":"Zhou","year":"2023","journal-title":"Stem Cell Res Ther"},{"key":"R28-20260905","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1002\/hep.31432","article-title":"M2 macrophage-derived exosomes facilitate HCC metastasis by transferring \u03b1M\u03b22 integrin to tumor cells","volume":"73","author":"Wu","year":"2021","journal-title":"Hepatology"},{"key":"R29-20260905","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biochi.2023.03.014","article-title":"Cancer stem cell-derived exosome-induced metastatic cancer: an orchestra within the tumor microenvironment","volume":"212","author":"Rashid","year":"2023","journal-title":"Biochimie"},{"key":"R30-20260905","doi-asserted-by":"crossref","first-page":"4252","DOI":"10.1111\/cas.15948","article-title":"Exosomal miR-222-3p contributes to castration-resistant prostate cancer by activating mTOR signaling","volume":"114","author":"Wang","year":"2023","journal-title":"Cancer Sci"},{"key":"R31-20260905","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.1073\/pnas.0510973103","article-title":"Synergistic roles of platelet-derived growth factor-BB and interleukin-1beta in phenotypic modulation of human aortic smooth muscle cells","volume":"103","author":"Chen","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R32-20260905","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1161\/CIRCRESAHA.111.261743","article-title":"Rare, nonsynonymous variant in the smooth muscle-specific isoform of myosin heavy chain, MYH11, R247C, alters force generation in the aorta and phenotype of smooth muscle cells","volume":"110","author":"Kuang","year":"2012","journal-title":"Circ Res"},{"key":"R33-20260905","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1161\/ATVBAHA.116.303229","article-title":"Altered smooth muscle cell force generation as a driver of thoracic aortic aneurysms and dissections","volume":"37","author":"Milewicz","year":"2017","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"R34-20260905","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/ncb2000","article-title":"Rab27a and Rab27b control different steps of the exosome secretion pathway","volume":"12","author":"Ostrowski","year":"2010","journal-title":"Nat Cell Biol"},{"key":"R35-20260905","doi-asserted-by":"crossref","first-page":"5005","DOI":"10.3390\/cimb45060318","article-title":"Impact of HepG2 cells glutathione depletion on neutral sphingomyelinases mRNA levels and activity","volume":"45","author":"Gamal","year":"2023","journal-title":"Curr Issues Mol Biol"},{"key":"R36-20260905","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1016\/j.bbamem.2006.06.025","article-title":"Neutral sphingomyelinases and nSMase2: bridging the gaps","author":"Clarke","year":"2006","journal-title":"Biochim Biophys Acta"},{"key":"R37-20260905","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1007\/s12017-010-8120-z","article-title":"Mammalian neutral sphingomyelinases: regulation and roles in cell signaling responses","volume":"12","author":"Wu","year":"2010","journal-title":"Neuromolecular Med"},{"key":"R38-20260905","doi-asserted-by":"crossref","first-page":"eaau6977","DOI":"10.1126\/science.aau6977","article-title":"The biology, function, and biomedical applications of exosomes","volume":"367","author":"Kalluri","year":"2020","journal-title":"Science"},{"key":"R39-20260905","doi-asserted-by":"crossref","first-page":"100095","DOI":"10.1016\/j.ynpai.2022.100095","article-title":"Interplay between exosomes and autophagy machinery in pain management: state of the art","volume":"12","author":"Morteza Bagi","year":"2022","journal-title":"Neurobiol Pain"},{"key":"R40-20260905","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/ncb2502","article-title":"Syndecan-syntenin-ALIX regulates the biogenesis of exosomes","volume":"14","author":"Baietti","year":"2012","journal-title":"Nat Cell Biol"},{"key":"R41-20260905","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.tcb.2016.11.003","article-title":"Extracellular vesicles: unique intercellular delivery vehicles","volume":"27","author":"Maas","year":"2017","journal-title":"Trends Cell Biol"},{"key":"R42-20260905","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1126\/science.1153124","article-title":"Ceramide triggers budding of exosome vesicles into multivesicular endosomes","volume":"319","author":"Trajkovic","year":"2008","journal-title":"Science"},{"key":"R43-20260905","doi-asserted-by":"crossref","first-page":"100435","DOI":"10.1016\/j.jlr.2023.100435","article-title":"Regulated translocation of neutral sphingomyelinase-2 to the plasma membrane drives insulin resistance in steatotic hepatocytes","volume":"64","author":"El-Amouri","year":"2023","journal-title":"J Lipid Res"},{"key":"R44-20260905","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s12094-022-02925-5","article-title":"Blockade of exosome release alters HER2 trafficking to the plasma membrane and gives a boost to trastuzumab","volume":"25","author":"Hosseini","year":"2023","journal-title":"Clin Transl Oncol"},{"key":"R45-20260905","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1007\/s12079-017-0421-7","article-title":"Pathways of production and delivery of hepatocyte exosomes","volume":"12","author":"Chen","year":"2018","journal-title":"J Cell Commun Signal"},{"key":"R46-20260905","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1002\/ijc.29542","article-title":"Guggulsterone and bexarotene induce secretion of exosome-associated breast cancer resistance protein and reduce doxorubicin resistance in MDA-MB-231 cells","volume":"137","author":"Kong","year":"2015","journal-title":"Int J Cancer"},{"key":"R47-20260905","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ceb.2015.04.013","article-title":"Extracellular vesicles shuffling intercellular messages: for good or for bad","volume":"35","author":"Lo","year":"2015","journal-title":"Curr Opin Cell Biol"},{"key":"R48-20260905","doi-asserted-by":"crossref","first-page":"115449","DOI":"10.1016\/j.biopha.2023.115449","article-title":"Therapeutic potential of mesenchymal stem cell-derived exosomal miR-296-5p and miR-337-3p in age-related erectile dysfunction via regulating PTEN\/PI3K\/AKT pathway","volume":"167","author":"Li","year":"2023","journal-title":"Biomed Pharmacother"},{"key":"R49-20260905","doi-asserted-by":"crossref","first-page":"13289","DOI":"10.1111\/jcmm.15946","article-title":"Exosomes derived from smooth muscle cells ameliorate diabetes-induced erectile dysfunction by inhibiting fibrosis and modulating the NO\/cGMP pathway","volume":"24","author":"Song","year":"2020","journal-title":"J Cell Mol Med"}],"container-title":["Asian Journal of Andrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.4103\/aja202569","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T09:00:45Z","timestamp":1788598845000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.4103\/aja202569"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,17]]},"references-count":49,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.4103\/aja202569","relation":{},"ISSN":["1008-682X","1745-7262"],"issn-type":[{"value":"1008-682X","type":"print"},{"value":"1745-7262","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,17]]},"assertion":[{"value":"2024-12-10","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-29","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}