{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:32:40Z","timestamp":1791361960053,"version":"4.3.1"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2012,9]]},"abstract":"<jats:sec>\n            <jats:title>Background and Purpose\u2014<\/jats:title>\n            <jats:p>Enhanced angiogenesis facilitates neurovascular remodeling processes and promotes brain functional recovery after stroke. Previous studies from our laboratory demonstrated that valproate (VPA), a histone deacetylase inhibitor, protects against experimental brain ischemia. The present study investigated whether VPA could enhance angiogenesis and promote long-term functional recovery after ischemic stroke.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods\u2014<\/jats:title>\n            <jats:p>Male rats underwent middle cerebral artery occlusion for 60 minutes followed by reperfusion for up to 14 days. Assessed parameters were: locomotor function through the Rotarod test; infarct volume through T2-weighted MRI; microvessel density through immunohistochemistry; relative cerebral blood flow through perfusion-weighted imaging; protein levels of proangiogenic factors through Western blotting; and matrix metalloproteinase-2\/9 activities through gelatin zymography.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results\u2014<\/jats:title>\n            <jats:p>Postischemic VPA treatment robustly improved the Rotarod performance of middle cerebral artery occlusion rats on Days 7 and 14 after ischemia and significantly reduced brain infarction on Day 14. Concurrently, VPA markedly enhanced microvessel density, facilitated endothelial cell proliferation, and increased relative cerebral blood flow in the ipsilateral cortex. The transcription factor hypoxia-inducible factor-1\u03b1 and its downstream proangiogenic factors, vascular endothelial growth factor and matrix metalloproteinase-2\/9, were upregulated after middle cerebral artery occlusion and significantly potentiated by VPA in the ipsilateral cortex. Acetylation of histone-H3 and H4 was robustly increased by chronic VPA treatment. The beneficial effects of VPA on Rotarod performance and microvessel density were abolished by hypoxia-inducible factor-1\u03b1 inhibition.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>Chronic VPA treatment enhances angiogenesis and promotes functional recovery after brain ischemia. These effects may involve histone deacetylase inhibition and upregulation of hypoxia-inducible factor-1\u03b1 and its downstream proangiogenic factors vascular endothelial growth factor and matrix metalloproteinase-2\/9.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.112.652545","type":"journal-article","created":{"date-parts":[[2012,7,18]],"date-time":"2012-07-18T22:16:34Z","timestamp":1342649794000},"page":"2430-2436","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":97,"title":["Chronic Valproate Treatment Enhances Postischemic Angiogenesis and Promotes Functional Recovery in a Rat Model of Ischemic Stroke"],"prefix":"10.1161","volume":"43","author":[{"given":"Zhifei","family":"Wang","sequence":"first","affiliation":[{"name":"From the Molecular Neurobiology Section, National Institute of Mental Health (Z.W., L.-K.T., Y.L., E.B.F., F.C., P.L., D.-M.C.) and Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke (J.M.), National Institutes of Health, Bethesda, MD; and the Departments of Neurology and Stroke Center, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (L.-K.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Kai","family":"Tsai","sequence":"additional","affiliation":[{"name":"From the Molecular Neurobiology Section, National Institute of Mental Health (Z.W., L.-K.T., Y.L., E.B.F., F.C., P.L., D.-M.C.) and Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke (J.M.), National Institutes of Health, Bethesda, MD; and the Departments of Neurology and Stroke Center, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (L.-K.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeeva","family":"Munasinghe","sequence":"additional","affiliation":[{"name":"From the Molecular Neurobiology Section, National Institute of Mental Health (Z.W., L.-K.T., Y.L., E.B.F., F.C., P.L., D.-M.C.) and Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke (J.M.), National Institutes of Health, Bethesda, MD; 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