{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T15:51:54Z","timestamp":1790178714440,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,13]],"date-time":"2025-09-13T00:00:00Z","timestamp":1757721600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fraternal Order of Eagles Diabetes Research Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Endothelial cell (EC) dysfunction is an early sign of compromised vascular integrity and is associated with various cardiovascular diseases (CVDs). Activation of Toll-like receptor 4 (TLR4) plays a central role in this process. Extracellular vesicles (EVs) derived from milk have known anti-inflammatory properties, particularly in suppressing TLR4 activation. This study investigates the therapeutic potential of human breast milk-derived EVs (HBM-EVs) in mitigating EC dysfunction related to CVDs. Methods: HBM-EVs were isolated from the breast milk of healthy nursing mothers using ultracentrifugation. HBM-EVs were applied to lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells (HUVECs), and inflammatory marker expression was assessed through qPCR and Western blotting. Mitochondrial oxidative stress was measured using MitoSOX. The effects of HBM-EVs were further evaluated in ex vivo studies using mesenteric arteries from diet-induced obese mice. Additionally, the effect of HBM-EVs on angiogenesis was tested via a wound closure assay. Results: In HUVECs, pre-treatment with HBM-EVs inhibited LPS-induced expression of inflammatory markers, including IL-6 and VCAM-1, as well as the phosphorylation of NF\u03baB. Additionally, HBM-EVs reduced LPS-induced mitochondrial oxidative stress. In animal studies, HBM-EV treatment restored EC-dependent vasorelaxation in mesenteric arteries from diet-induced obese mice. Furthermore, HBM-EVs enhanced EC migration, leading to improved wound closure in HUVECs. Conclusion: This study demonstrates the therapeutic potential of HBM-EVs in alleviating EC dysfunction, offering a promising new approach to the treatment of CVDs. Future research will focus on identifying the specific cargo of HBM-EVs and further exploring their therapeutic mechanisms in endothelial dysfunction.<\/jats:p>","DOI":"10.3390\/nu17182953","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T09:43:41Z","timestamp":1757929421000},"page":"2953","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Human Breast Milk Extracellular Vesicles Mitigate Endothelial Dysfunction"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3017-6990","authenticated-orcid":false,"given":"Young-Eun","family":"Cho","sequence":"first","affiliation":[{"name":"College of Nursing, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoshuai","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Nursing, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Crouch","sequence":"additional","affiliation":[{"name":"College of Nursing, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damon","family":"Shutt","sequence":"additional","affiliation":[{"name":"College of Nursing, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin W.","family":"Kaufman","sequence":"additional","affiliation":[{"name":"Stead Family Department of Pediatrics, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5311-543X","authenticated-orcid":false,"given":"Brajesh K.","family":"Singh","sequence":"additional","affiliation":[{"name":"Stead Family Department of Pediatrics, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1161\/ATVBAHA.120.314346","article-title":"Exploring the Role of Endothelial Cell Resilience in Cardiovascular Health and Disease","volume":"41","author":"Gao","year":"2021","journal-title":"Arterioscler. 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