{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:02:19Z","timestamp":1785412939114,"version":"3.56.0"},"reference-count":47,"publisher":"IMR Press","issue":"7","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003787","name":"Hebei Provincial Natural Science Foundation of China","doi-asserted-by":"crossref","award":["H2019206406"],"award-info":[{"award-number":["H2019206406"]}],"id":[{"id":"10.13039\/501100003787","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Integr. Neurosci."],"abstract":"<jats:p>Background:Stroke remains a leading cause of death and disability worldwide. Endothelial dysfunction plays a central role in both acute ischemic injury and subsequent recovery. In this study, we investigated the protective effects and underlying mechanisms of Dl-3-n-butylphthalide (NBP) on human brain microvascular endothelial cells (HBMECs) subjected to oxygen-glucose deprivation (OGD), an in vitro model of ischemic stroke.Methods:HBMECs were divided into three groups: control (normoxia), OGD (10 h hypoxia, followed by reoxygenation for different durations (0\u201324 h), and then a subsequent 24 h incubation), and NBP-treated OGD (10 \u03bcmol\/L NBP during reoxygenation). Cell viability and apoptosis were assessed by Cell Counting Kit 8 (CCK8), lactate dehydrogenase (LDH) release, and flow cytometry. Mitochondrial function was evaluated using MitoTracker fluorescence. Molecular mechanisms were examined using Western blot, quantitative real-time PCR (qRT-PCR), immunofluorescence, and enzyme-linked immunosorbent assay (ELISA), focusing on the hypoxia-inducible factor-1\u03b1 (HIF1\u03b1)\/vascular endothelial growth factor (VEGF) angiogenic pathway and cyclooxygenase-2 (COX2)-mediated inflammatory response.Results:NBP at 10 \u03bcmol\/L significantly improved HBMEC viability (37.5% increase, p &lt; 0.01), reduced apoptosis (p &lt; 0.01), and restored mitochondrial membrane potential (p &lt; 0.05) following OGD injury. Mechanistically, NBP demonstrated dual pathway modulation by: (1) promoting angiogenesis-related gene expression through HIF1\u03b1 upregulation and subsequent increase in vascular endothelial growth factor receptor 2 (VEGFR2) and endothelial nitric oxide synthase (eNOS) expression (p &lt; 0.05); and (2) suppressing inflammation via COX2 downregulation with concurrent reduction of downstream mediators including inducible nitric oxide synthase (iNOS), tumor necrosis factor-\u03b1 (TNF\u03b1), interleukin-1\u03b2 (IL-1\u03b2), and Thromboxane B2 (TXB2, p &lt; 0.05). This coordinated regulation created a favorable microenvironment balancing pro-angiogenic signals with anti-inflammatory effects.Conclusion:NBP exerts multi-targeted protection on HBMECs after ischemic injury through associated with the activation of HIF1\u03b1\/VEGF-mediated angiogenesis and suppression of COX2-driven inflammation. This dual modulation strategy, targeting both vascular repair and inflammatory control, provides preliminary in vitro mechanistic insights that warrant further validation in vivo and in clinical settings.<\/jats:p>","DOI":"10.31083\/jin51032","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:01:26Z","timestamp":1785409286000},"source":"Crossref","is-referenced-by-count":0,"title":["Dl-3-n-Butylphthalide Protects Human Brain Microvascular Endothelial Cells Against Ischemic Injury Through Dual Modulation of HIF1\u03b1\/VEGF-Mediated Angiogenesis and COX2-Mediated Inflammation"],"prefix":"10.31083","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8842-9699","authenticated-orcid":true,"given":"Yanyan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurology, The Second Hospital of Hebei Medical University, 050000 Shijiazhuang, Hebei, China"},{"name":"The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, 050000 Shijiazhuang, Hebei, China"},{"name":"Neurological Laboratory of Hebei Province, 050000 Shijiazhuang, Hebei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6160-5564","authenticated-orcid":true,"given":"Chuanxin","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Peking University People's Hospital Qingdao Hospital, 266011 Qingdao, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6331-2443","authenticated-orcid":true,"given":"Teng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Hospital of Hebei Medical University, 050000 Shijiazhuang, Hebei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8361-2947","authenticated-orcid":true,"given":"Shijia","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of System Medicine, Zhejiang University School of Medicine, 310000 Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0647-5429","authenticated-orcid":true,"given":"Zhenzhong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Hospital of Hebei Medical University, 050000 Shijiazhuang, Hebei, China"},{"name":"The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, 050000 Shijiazhuang, Hebei, China"},{"name":"Neurological Laboratory of Hebei Province, 050000 Shijiazhuang, Hebei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9698-3485","authenticated-orcid":true,"given":"Lihong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Hospital of Hebei Medical University, 050000 Shijiazhuang, Hebei, China"},{"name":"The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, 050000 Shijiazhuang, Hebei, China"},{"name":"Neurological Laboratory of Hebei Province, 050000 Shijiazhuang, Hebei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Feigin VL, Brainin M, Norrving B, Martins S, Sacco RL, Hacke W, et al. 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