["The Journal of Physiology, Volume 604, Issue 11, Page 4151-4165, 1 June 2026. ", "\nAbstract figure legend The study assessed plasma‐derived extracellular vesicles (EVs) from control patients and those with first‐ever ischaemic stroke, divided into mild and severe groups. Stroke patients had lower EV concentrations than controls, with mild‐stroke patients showing fewer and smaller EVs. Stroke‐derived EVs exhibited elevated levels of proinflammatory markers (IL‐6, interleukin 6; TNF‐α, tumour necrosis factor α), oxidative stress markers (NTR, nitrotyrosine), and angiogenic factors (VEGF, vascular endothelial growth factor) but lower levels of placental growth factor (PlGF) than controls. Some differences were observed between mild‐ and severe‐stroke‐derived EVs. Thus severe‐stroke EVs have a higher level of VEGF, whereas mild‐stroke EVs have higher levels of IL‐6. Therefore severe‐stroke EVs enhanced angiogenesis more significantly than those from mild‐stroke or control groups. In an in vitro blood–brain barrier (BBB) model, EVs from severe‐stroke patients caused less disruption and increased the expression of claudin‐5 (CLDN5) protein, suggesting that these EVs may support BBB integrity while promoting angiogenesis. \n\n\n\n\n\n\n\n\n\nAbstract\nIschaemic stroke is a leading cause of death and disability. Circulating extracellular vesicles (EVs) post‐stroke may help brain endothelial cells (BECs) counter ischaemic injury. However data on how EVs from ischaemic stroke patients, considering injury severity, affect these cells are limited. The aims were to characterize the inflammatory and angiogenic components of circulating EVs in acute ischaemic stroke patients, considering stroke severity, and to investigate whether these circulating EVs differentially influence the proangiogenic properties and blood–brain barrier (BBB) integrity of human BECs. Eighteen ischaemic stroke patients (acute phase: 24–48 h) and nine controls matched by age, sex, and blood pressure were studied. Stroke severity was classified as severe (n = 9) or mild (n = 9). Plasma EVs were analysed for size, concentration, and protein markers (CD63, Alix, CD81, TSG101, HSP70), as well as proinflammatory and angiogenic proteins. EV uptake, cell viability, proangiogenic capacity, electrical resistance [TEER (transendothelial electrical resistance)], and dextran‐70 kD permeability were assessed using human brain microvascular endothelial cells (hCMEC/D3). Stroke patients had lower EV concentrations than controls (p = 0.075), with mild‐stroke patients having the smallest EVs. Stroke‐derived EVs had higher levels of interleukin 6 (IL‐6), tumour necrosis factor α (TNF‐α), nitrotyrosine, and vascular endothelial growth factor (VEGF) but lower placental growth factor (PLGF) compared to controls. IL‐6 was higher in mild strokes (p = 0.0025), and VEGF was higher in severe strokes (p = 0.048). EVs from severe‐stroke cases enhanced proangiogenic capacity and minimally disrupted the BBB. Stroke severity influences EV number, size, and composition. EVs from severe strokes may promote BBB restoration and cerebral angiogenesis, suggesting their role in intercellular communication and homeostasis in ischaemic tissue.\n\n\n\n\n\n\n\n\n\nKey points\n\nIschaemic stroke is one of the leading causes of death worldwide. After an ischaemic stroke several physiological processes are triggered to recover the injured tissue.\nIncreasing evidence has suggested that extracellular vesicles (EVs) present in the bloodstream could play a role in brain recovery, but their specific impact, especially concerning stroke severity, was unclear.\nThis study demonstrates that plasma‐derived EVs from first‐ever ischaemic stroke patients have distinctive characteristics and effects over brain angiogenesis and blood–brain barrier (BBB) integrity.\nOur study proposes that circulating EVs from patients with severe stroke may carry protective factors to initiate brain endothelial cell recovery after acute episodes.\nThese findings underscore the role of EVs as potential effectors of BBB recovery and biomarkers in severe ischaemic stroke.\n\n\n"]