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PRP-derived EVs from treadmill-loaded and sedentary rats were designated athletes (aPRP-EVs) and non-athlete (nPRP-EVs), respectively. Both were administered to primary cortical neurons exposed to oxygen-glucose deprivation (OGD) and to adult male Wistar\/ST rats subjected to permanent middle cerebral artery occlusion (MCAO). Exercise increased CD63, CD31, and transforming growth factor-\u03b21 (TGF-\u03b21) in PRP-derived EVs. In OGD-exposed neurons, aPRP-EVs enhanced viability, elevated phosphorylated neurofilament heavy chain, and reduced intracellular calcium. Canonical pathway analysis showed upregulated TGF-\u03b2\/SMAD signaling in EV groups versus vehicle, while \u2018Ca signaling\u2019 was downregulated in aPRP-EVs versus nPRP-EVs. In MCAO rats, EVs improved neurological and motor function and reduced neuronal apoptosis at 28 days, with aPRP-EVs promoting earlier, greater recovery and infarct reduction. These effects correlated with TGF-\u03b21 upregulation, SMAD4 nuclear translocation, reduced NMDAR2B expression, and enhanced axonal growth in the peri-infarct region. PRP-derived EVs, particularly from exercise-trained donors, enhance neuroregeneration and functional recovery in chronic ischemic stroke via TGF-\u03b2\/SMAD and calcium signaling modulation.<\/jats:p>","DOI":"10.1177\/0271678x251369219","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T11:34:06Z","timestamp":1755689646000},"page":"359-376","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":5,"title":["Exercise-induced extracellular vesicles derived from platelet-rich plasma improved recovery after ischemic stroke"],"prefix":"10.1177","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7787-7718","authenticated-orcid":false,"given":"Yoshifumi","family":"Miyauchi","sequence":"first","affiliation":[{"name":"Department of Neurology, Juntendo University Faculty of Medicine, Tokyo, 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