{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:46:11Z","timestamp":1791899171560,"version":"4.3.4"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Angiogenesis contributes to vascular repair and functional recovery after ischemic stroke, yet how nitric oxide\u2013mediated S-nitrosylation shapes this response remains unclear. We investigated the role of S-nitrosylation in postischemic angiogenesis and the underlying molecular mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>S-nitrosylation proteomics was performed in ischemic brain tissue from 8-week-old male mice subjected to transient middle cerebral artery occlusion and in brain microvascular endothelial cells exposed to oxygen-glucose deprivation\/reoxygenation. Candidate modification sites were validated by cysteine mutagenesis and biotin-switch assays. Wild-type and C339A-mutant FKBP5 (FK506-binding protein 5) were compared in endothelial angiogenesis assays. Four-week-old male mice received endothelial-targeted adeno-associated virus 9 encoding wild-type or C339A-mutant FKBP5 and underwent transient middle cerebral artery occlusion 4 weeks later. Vascular and neurological outcomes were assessed through day 28. Protein-interaction and signaling analyses defined the downstream mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>S-nitrosylated FKBP5, but not total FKBP5, was increased in ischemic brain tissue and oxygen-glucose deprivation\/reoxygenation-treated endothelial cells; inducible nitric oxide synthase was an upstream mediator. Mass spectrometry and mutagenesis identified cysteine 339 as the predominant modification site. C339A prevented FKBP5 S-nitrosylation and rescued endothelial proliferation, migration, sprouting, and tube formation after oxygen-glucose deprivation\/reoxygenation. In mice, endothelial-targeted expression of FKBP5-C339A promoted peri-infarct angiogenesis and perfusion, reduced tissue injury, and improved chronic sensorimotor recovery. Mechanistically, S-nitrosylation strengthened FKBP5 binding to PHLPP (PH domain leucine-rich repeat protein phosphatase) and reduced AKT (serine\/threonine kinase) phosphorylation. C339A weakened this interaction and restored AKT activation, whereas PHLPP inhibition with NSC117079 enhanced AKT signaling and angiogenic responses in vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>We identify endothelial FKBP5 as a previously unrecognized regulator of poststroke vascular regeneration and establish S-nitrosylation at cysteine 339 as a molecular switch that restrains angiogenesis and functional recovery through PHLPP-dependent inhibition of AKT signaling. Targeting this modification may offer a strategy to enhance vascular repair after ischemic stroke.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.126.056196","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T09:00:47Z","timestamp":1787907647000},"page":"3106-3123","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["S-Nitrosylation of Endothelial FK506-Binding Protein 5 Impairs Angiogenesis via PHLPP-AKT Axis in Ischemic Stroke"],"prefix":"10.1161","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4544-6893","authenticated-orcid":true,"given":"Xi-Yue","family":"Zhang","sequence":"first","affiliation":[{"name":"Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, China (X.-Y.Z., H.X., W.G., H.-L.W., Z.-H.S., Y.-Y.L., H.-L.X., J.J., X.-L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Xu","sequence":"additional","affiliation":[{"name":"Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, China (X.-Y.Z., H.X., W.G., H.-L.W., Z.-H.S., Y.-Y.L., H.-L.X., J.J., X.-L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Guo","sequence":"additional","affiliation":[{"name":"Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, China (X.-Y.Z., H.X., W.G., H.-L.W., Z.-H.S., Y.-Y.L., H.-L.X., J.J., X.-L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua-Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, China (X.-Y.Z., H.X., W.G., H.-L.W., Z.-H.S., Y.-Y.L., H.-L.X., J.J., X.-L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Hui","family":"Sun","sequence":"additional","affiliation":[{"name":"Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, China (X.-Y.Z., H.X., W.G., H.-L.W., Z.-H.S., Y.-Y.L., H.-L.X., J.J., X.-L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, China (X.-Y.Z., H.X., W.G., H.-L.W., Z.-H.S., Y.-Y.L., H.-L.X., J.J., X.-L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-Lian","family":"Xiao","sequence":"additional","affiliation":[{"name":"Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, China (X.-Y.Z., H.X., W.G., H.-L.W., Z.-H.S., Y.-Y.L., H.-L.X., J.J., X.-L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Ji","sequence":"additional","affiliation":[{"name":"Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, China (X.-Y.Z., H.X., W.G., H.-L.W., Z.-H.S., Y.-Y.L., H.-L.X., J.J., X.-L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8741-3833","authenticated-orcid":true,"given":"Xiu-Lan","family":"Sun","sequence":"additional","affiliation":[{"name":"Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, China (X.-Y.Z., H.X., W.G., H.-L.W., Z.-H.S., Y.-Y.L., H.-L.X., J.J., X.-L.S.)."},{"name":"Nanjing University of Chinese Medicine, China 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