{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T11:30:40Z","timestamp":1786707040593,"version":"build-2736575974"},"reference-count":32,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Korean Fund for Regenerative Medicine","award":["RS-2022-00070517"],"award-info":[{"award-number":["RS-2022-00070517"]}]},{"name":"Korean Fund for Regenerative Medicine","award":["RS-2026-25502866"],"award-info":[{"award-number":["RS-2026-25502866"]}]},{"name":"S&E bio Co., Ltd."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Moyamoya disease (MMD) is a progressive cerebrovascular disorder characterized by intracranial arterial stenosis and abnormal collateral vessel formation. The molecular mechanisms by which extracellular vesicle (EV)-derived microRNAs contribute to endothelial dysfunction remain poorly understood. We investigated whether circulating extracellular vesicle-derived microRNAs (EV-miRNAs) contribute to endothelial dysfunction and serve as functional mediators of MMD pathogenesis. Plasma EV-miRNA profiles were compared among patients with MMD, intracranial atherosclerosis (ICAS), and healthy controls, and differentially expressed EV-miRNAs were validated in an independent cohort. Functional studies were performed in human umbilical vein endothelial cells and patient-derived induced pluripotent stem cell-derived endothelial cells. Three EV-miRNAs were significantly upregulated in MMD, among which miR-558 showed the strongest diagnostic performance. miR-558 overexpression impaired endothelial tube formation and proliferation, whereas its inhibition enhanced angiogenic activity. Mechanistically, HMGB2 was identified as a direct target of miR-558, and miR-558 overexpression reduced HMGB2 protein expression. Patient-derived endothelial cells recapitulated increased miR-558 expression, reduced HMGB2 levels, and impaired angiogenic capacity. These findings identify circulating EV-miR-558 a potential biomarker and show that miR-558 suppresses HMGB2 and impairs endothelial angiogenesis in adult MMD, suggesting that the EV-miR-558\/HMGB2 pathway represents a potential mechanism underlying endothelial dysfunction and therapeutic target for MMD.<\/jats:p>","DOI":"10.3390\/cells15161456","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T17:01:35Z","timestamp":1786640495000},"page":"1456","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Extracellular Vesicle miR-558 Regulates Endothelial Function Through HMGB2 in Adult Moyamoya Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1580-3204","authenticated-orcid":false,"given":"Eun Hee","family":"Kim","sequence":"first","affiliation":[{"name":"S&E bio Co., Ltd., Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oh Young","family":"Bang","sequence":"additional","affiliation":[{"name":"S&E bio Co., Ltd., Seoul 06351, Republic of Korea"},{"name":"Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center, Seoul 06351, Republic of Korea"},{"name":"Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3119-6045","authenticated-orcid":false,"given":"Gyun Sik","family":"Oh","sequence":"additional","affiliation":[{"name":"S&E bio Co., Ltd., Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi Jeong","family":"Oh","sequence":"additional","affiliation":[{"name":"Translational and Stem Cell Research Laboratory on Stroke, Samsung Medical Center, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo Joo","family":"Lee","sequence":"additional","affiliation":[{"name":"S&E bio Co., Ltd., Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Jea","family":"Sung","sequence":"additional","affiliation":[{"name":"Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong-Won","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4004-8434","authenticated-orcid":false,"given":"Woo-Keun","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyeong-Moon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Keun","family":"Jee","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4603-8103","authenticated-orcid":false,"given":"Je Young","family":"Yeon","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong-Soo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiho","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Medical Convergence, Catholic Kwandong University, Gangneung-si 25601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/S1474-4422(22)00165-X","article-title":"Moyamoya disease: Diagnosis and interventions","volume":"21","author":"Ihara","year":"2022","journal-title":"Lancet 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