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Neoagarotetraose (NA4), a marine-derived oligosaccharide, possesses potent antioxidant activity, but its effects on hypertension remain unexplored. Here, we investigated the role of NA4 in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and in SHR in vivo. NA4 treatment significantly reduced mitochondrial superoxide, H2O2 levels, and NADPH oxidase activity in SHR-VSMCs and suppressed their hyperproliferation and migration. RNA-seq identified FoxO4 as a significantly downregulated target. FoxO4 overexpression enhanced ROS production and VSMC dysfunction, and these effects were reversed by NA4. In SHR, oral administration of NA4 (200 or 250 mg\/kg\/day) for 4 weeks lowered blood pressure, attenuated vascular remodeling, and reduced arterial FoxO4 expression and superoxide generation. Collectively, NA4 ameliorates hypertensive vascular remodeling, and molecular docking suggests a potential interaction between NA4 and the FoxO4-ROS axis, highlighting its potential as a functional food ingredient for hypertension management.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c04509","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T12:21:48Z","timestamp":1780921308000},"page":"18072-18084","source":"Crossref","is-referenced-by-count":0,"title":["Neoagarotetraose\nfrom Marine Red Algae Attenuates\nHypertensive Vascular Remodeling by Targeting FoxO4 to Inhibit Mitochondrial\nSuperoxide Generation"],"prefix":"10.1021","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5594-5042","authenticated-orcid":true,"given":"Nan","family":"Wu","sequence":"first","affiliation":[{"name":"Third Institute of Oceanography, Ministry of Natural Resources , , ,","place":["Xiamen, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaocheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Third Institute of Oceanography, Ministry of Natural Resources , , ,","place":["Xiamen, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yating","family":"Du","sequence":"additional","affiliation":[{"name":"Third Institute of Oceanography, Ministry of Natural Resources , , ,","place":["Xiamen, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuhua","family":"Chan","sequence":"additional","affiliation":[{"name":"Third Institute of Oceanography, Ministry of Natural Resources , , ,","place":["Xiamen, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runying","family":"Zeng","sequence":"additional","affiliation":[{"name":"Third Institute of Oceanography, Ministry of Natural Resources , , ,","place":["Xiamen, China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"issue":"7","key":"2026073021174307000_cit1","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1161\/CIRCRESAHA.121.318063","article-title":"Oxidative Stress and Hypertension.","volume":"128","author":"Griendling","year":"2021","journal-title":"Circulation research"},{"key":"2026073021174307000_cit2","doi-asserted-by":"publisher","first-page":"119942","DOI":"10.1016\/j.lfs.2021.119942","article-title":"Reactive oxygen species:\nRole in carcinogenesis, cancer cell signaling and tumor progression.","volume":"284","author":"Sarmiento-Salinas","year":"2021","journal-title":"Life sciences"},{"issue":"4","key":"2026073021174307000_cit3","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1161\/HYPERTENSIONAHA.117.07802","article-title":"Oxidative Stress, Inflammation, and Vascular Aging\nin Hypertension.","volume":"70","author":"Guzik","year":"2017","journal-title":"Hypertension (Dallas, Tex.:\n1979)"},{"issue":"3","key":"2026073021174307000_cit4","doi-asserted-by":"publisher","first-page":"H613","DOI":"10.1152\/ajpheart.00220.2020","article-title":"Metabolism\nof vascular smooth muscle cells in vascular diseases.","volume":"319","author":"Shi","year":"2020","journal-title":"American journal of physiology. 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Pharmacother."},{"key":"2026073021174307000_cit33","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2025.1538472","article-title":"FOXOs and\ntheir roles in acute and chronic neurological disorders","volume":"12","author":"Asadi","year":"2025","journal-title":"Front. Mol. 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