Stroke最新文献

{"title":"Stroke Prevention in the Longevity Era: An Integrated Framework for Cerebrovascular and Biological Aging.","authors":"Gustavo Saposnik, Conrado E Estol","doi":"10.1161/STROKEAHA.126.056919","DOIUrl":"https://doi.org/10.1161/STROKEAHA.126.056919","url":null,"abstract":"","PeriodicalId":21989,"journal":{"name":"Stroke","volume":"57 10","pages":"3213-3218"},"PeriodicalIF":11.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guidelines in Action: Mental Health After Stroke.","authors":"Natalie Neale, Cathra Halabi","doi":"10.1161/STROKEAHA.126.056214","DOIUrl":"10.1161/STROKEAHA.126.056214","url":null,"abstract":"","PeriodicalId":21989,"journal":{"name":"Stroke","volume":" ","pages":"e499-e502"},"PeriodicalIF":11.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148832391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ticagrelor-Aspirin With Thrombolysis by Infarct Patterns in Moderate Ischemic Stroke: TAPIS Subgroup Analysis.","authors":"Xiaohui Zi, Yong He, Guojuan Chen, Qinghua Wang, Xue Xia, Jing Li, Xiaoli Zhang, Jing Jing, Philip M Bath, Guillaume Turc, Anxin Wang, Yilong Wang","doi":"10.1161/STROKEAHA.126.057001","DOIUrl":"10.1161/STROKEAHA.126.057001","url":null,"abstract":"<p><strong>Background: </strong>Whether diffusion‑weighted imaging infarction patterns influence the efficacy and safety of early oral ticagrelor‑aspirin with intravenous thrombolysis in moderate acute ischemic stroke is uncertain. We assessed treatment effects by infarction pattern in this thrombolysis setting.</p><p><strong>Methods: </strong>This was a subgroup analysis of the TAPIS trial (Ticagrelor With Aspirin Dual Antiplatelet Therapy Combined With Intravenous Thrombolysis in Patients With Ischemic Stroke), a 60-center, randomized, double‑blind trial in China. Patients aged 18 to 80 years with noncardioembolic stroke (National Institutes of Health Stroke Scale score 4-10) who received intravenous thrombolysis within 4.5 hours of onset were randomized within 6 hours to ticagrelor‑aspirin or placebo. Diffusion‑weighted imaging patterns were centrally adjudicated as multiple acute infarcts (MAIs; ≥2 lesions) or non‑MAIs (single infarction or diffusion‑weighted imaging-negative). The primary efficacy outcome was modified Rankin Scale score of 0 to 1 at 90 days; safety outcome was symptomatic intracranial hemorrhage. Treatment‑by‑pattern interaction was assessed.</p><p><strong>Results: </strong>Among 1307 patients (94.6% of full analysis set; median age, 65.5 years; 71.2% men; median National Institutes of Health Stroke Scale score, 6.0), 409 (31.3%) had MAIs and 898 (68.7%) non‑MAIs (20.8% diffusion‑weighted imaging-negative, 79.2% single infarction). MAIs were associated with poorer prognosis than non‑MAIs (excellent outcome: 58.9% versus 69.2%; adjusted risk ratio, 0.92 [95% CI, 0.84-1.00]). Ticagrelor‑aspirin was associated with a higher likelihood of excellent outcome versus placebo in MAIs (64.4% versus 53.4%; risk ratio, 1.21 [95% CI, 1.02-1.42]), whereas no significant benefit was observed in non‑MAIs (71.2% versus 67.1%; risk ratio, 1.06 [95% CI, 0.97-1.16]; <i>P</i>_interaction=0.18). Early neurological improvement showed significant heterogeneity by infarction pattern (<i>P</i>_interaction=0.02); the treatment‑by‑pattern interaction for the primary outcome was nominally significant after adjusting for rescue tirofiban use (<i>P</i>=0.04). Symptomatic intracranial hemorrhage occurred in MAIs: 1 of 205 (0.5%) versus 2 of 204 (1.0%); non‑MAIs: 1 of 448 (0.2%) versus 1 of 450 (0.2%).</p><p><strong>Conclusions: </strong>In thrombolyzed patients with moderate noncardioembolic stroke, MAIs were associated with poorer functional outcomes. Early ticagrelor‑aspirin showed directionally consistent benefits without excess bleeding in patients with MAIs, though the primary interaction was not significant. These hypothesis‑generating findings may inform future trials of diffusion‑weighted imaging infarction pattern as an imaging biomarker to guide antiplatelet therapy in early reperfusion.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT06316570.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":" ","pages":"2958-2970"},"PeriodicalIF":11.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intraarterial Thrombolysis: Past, Present, Future.","authors":"Felix C Ng, Chengchuan Wu, Ángel Chamorro, Wenjie Zi, Xiaochuan Huo, Bernard Yan, Yamei Tang, Raul G Nogueira, Zhenhua Zhou, Urs Fischer, Johannes Kaesmacher, Benjamin Gory, Guillaume Turc, Sébastien Richard, Peter J Mitchell, Bruce C V Campbell","doi":"10.1161/STROKEAHA.126.052342","DOIUrl":"10.1161/STROKEAHA.126.052342","url":null,"abstract":"<p><p>Suboptimal clinical outcomes are common after ischemic stroke with large vessel occlusion despite current reperfusion treatment with intravenous thrombolysis and mechanical thrombectomy. Targeting residual distal arterial and microvascular occlusions with intraarterial thrombolysis has recently gained substantial interest as an adjunct to improve cerebral tissue perfusion. While recent trials provide promise in selected patients with anterior-circulation stroke, further high-quality, large-scale studies and pooled individual-patient analyses are needed. This review summarizes the evolving role of intraarterial thrombolysis over the past 3 decades and projects potential developments.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":" ","pages":"3159-3169"},"PeriodicalIF":11.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148760124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Projection of Stroke Incidence and Costs in China: 2022 to 2050.","authors":"Yutong Jiang, Lizheng Xu, Xia Wang, Meiqiyang Xue, Mingsheng Chen, Lei Si","doi":"10.1161/STROKEAHA.125.054522","DOIUrl":"10.1161/STROKEAHA.125.054522","url":null,"abstract":"<p><strong>Background: </strong>Stroke imposes a substantial and growing health and economic burden in China, yet forward-looking estimates of stroke-related costs remain scarce.</p><p><strong>Methods: </strong>Annual age- and sex-specific incidence rates of ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage were projected from 2022 to 2050 using 2021 as the baseline year. Baseline incidence estimates were obtained from the Global Burden of Disease 2021 database, and future trends were projected using an exponential growth model parameterized by the average annual percent change estimated from 1990 to 2021 Global Burden of Disease data. Projected incidence rates were combined with China-specific population projections. A deterministic decision-tree model was used to estimate hospitalization costs, direct medical costs, and societal costs over a 12-month time horizon in China, using probabilities and unit costs from published literature. We used uncertainty intervals (UI) to quantify the plausible range of all projected outcomes. One-way sensitivity analyses were conducted to assess uncertainty in epidemiological and cost parameters.</p><p><strong>Results: </strong>Total incident strokes are projected to increase from 4.35 million (95% UI, 3.09-5.89 million) in 2022 to 9.59 million (95% UI, 6.81-13.01 million) in 2050. By 2050, ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage incidences are projected to reach 7.89, 1.59, and 0.11 million, respectively. Total annual stroke hospitalization costs are projected to rise from $46.1 billion (95% UI, 44.94-47.24 billion) in 2022 to $91.2 billion (95% UI, 89.28-93.13 billion) in 2050; direct medical costs and societal costs are projected to increase from $67.6 billion to $133.9 billion and from $145.6 billion to $288.4 billion, respectively. Costs will be increasingly concentrated among adults aged ≥65 years, especially those aged ≥85 years. In 2050, stroke costs among men are projected to be approximately 1.3 times those for women. In sensitivity analyses incorporating incidence uncertainty, total annual hospitalization costs ranged from $39.9-$62.3 billion in 2022 to $65.0-$123.6 billion in 2050.</p><p><strong>Conclusions: </strong>Stroke incidence and costs in China are projected to increase through 2050, driven primarily by ischemic stroke and population aging, highlighting the need for targeted prevention, capacity planning for older adults, and long-term financing strategies.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":" ","pages":"3081-3090"},"PeriodicalIF":11.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eligibility for Thrombolysis for Pediatric Acute Ischemic Stroke.","authors":"Romain C Briest, Kartik D Bhatia, Christina Miteff, Andrew Cheung, Jayne Antony, Simone Ardern-Holmes, Ann M Bye, Michael Cardamone, Denise L Chan, Russell C Dale, Michelle A Farrar, Deepak Gill, Sachin Gupta, Alexandra Johnson, Tejaswi Kandula, John Lawson, Nathan W Manning, Alexander McQuinn, Manoj P Menezes, Ferdinand Miteff, Sekhar C Pillai, Hugo Sampaio, Robert L Smith, Gopinath Musuwadi Subramanian, Hooi Ling Teoh, Christopher Troedson, Richard I Webster, Jason Wenderoth, Justin Whitley, P Ian Andrews","doi":"10.1161/STROKEAHA.125.054223","DOIUrl":"10.1161/STROKEAHA.125.054223","url":null,"abstract":"<p><strong>Background: </strong>Thrombolysis is infrequently delivered to children with acute ischemic strokes (AIS). We explored potential eligibility for treatment with tPA (tissue-type plasminogen activator) for pediatric AIS.</p><p><strong>Methods: </strong>This retrospective, multicenter, observational, cohort study reviewed children aged 29 days to 17 years with symptomatic AIS identified via Children's Hospital Westmead, John Hunter Children's Hospital, and Sydney Children's Hospital between January 1, 2010, and December 31, 2019. Medical records were examined to evaluate eligibility for treatment with tPA based on established multinational and the 2026 American Heart Association guidelines, reasons for exclusion beyond delay to diagnosis, and long-term outcomes as pediatric modified Rankin Scale scores. We also explored additional exclusions and outcomes among children with small-vessel AIS and AIS in the context of brain tumors, who are currently excluded from tPA.</p><p><strong>Results: </strong>A total of 135 patients with 139 symptomatic AIS were identified-median age, 6 years; 36% female patients; 73% presented via emergency departments; mean follow-up, 43 months; 12% deaths. Irrespective of delay to diagnosis, only 26 of 139 (19%) AIS were potentially eligible for treatment with tPA. Among patients potentially eligible for tPA, acute neuroimaging revealed large-vessel occlusions, unilateral focal cerebral arteriopathy, or extracranial dissections. Thirteen of 26 (50%) had nondisabled outcomes without tPA treatment. One hundred thirteen of 139 (81%) AIS were ineligible for treatment with tPA, irrespective of delay to diagnosis. All deaths occurred among patients excluded from tPA, predominantly related to underlying disorders. Fifty-four small-vessel AIS accounted for 39% of AIS. Eighteen (33%) had no additional ineligibilities to thrombolysis, among whom 10 had nondisabled outcomes without tPA.</p><p><strong>Conclusions: </strong>Based on current recommendations, 19% of symptomatic childhood AIS were potentially eligible for treatment with tPA, irrespective of delay to diagnosis. Selected patients with small-vessel AIS may offer an opportunity to extend the role of tPA. These observations may be relevant for optimizing pediatric stroke management strategies.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":" ","pages":"3000-3009"},"PeriodicalIF":11.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148832187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Colchicine for Secondary Prevention After Stroke According to the Presence of Atherosclerosis.","authors":"John J McCabe, Robin Lemmens, Francisco Purroy, Cathal Walsh, Christian Weimar, Anna Czlonkowska, Urs Fischer, Ana Catarina Fonseca, Michael D Hill, Dalius Jatuzis, Janika Kõrv, Christina Kruuse, Robert Mikulik, Darius Navabi, Joseph Harbison, Margaret O'Connor, Helle Klingenberg Iversen, Katja Adie, Paul Nederkoorn, Christopher Price, Peter J Kelly","doi":"10.1161/STROKEAHA.126.056561","DOIUrl":"10.1161/STROKEAHA.126.056561","url":null,"abstract":"<p><strong>Background: </strong>Anti-inflammatory therapies reduce the risk of major adverse cardiovascular events (MACEs) in coronary disease, but efficacy has not been shown after stroke. It is uncertain if patients with atherosclerosis are more likely to benefit from anti-inflammatory prevention.</p><p><strong>Methods: </strong>We performed a post hoc analysis of the CONVINCE trial (randomized, open-label, blinded-end point assessed; Colchicine for Prevention of Vascular Inflammation in Non-Cardioembolic Stroke), comparing colchicine 0.5 mg plus usual care versus usual care. We performed a subgroup analysis in patients stratified according to the presence/absence of atherosclerosis (defined as cervico-cranial/aortic artery plaque, coronary disease, peripheral arterial disease, and carotid revascularization). The primary outcome was MACE. Analyses were adjusted for age, qualifying event, time from event to randomization, and coronary disease.</p><p><strong>Results: </strong>Three thousand one hundred forty-four participants were included. There were 338 MACE events during follow-up (median, 33.6 months). On intention-to-treat analysis, there were numerically fewer MACE events in the atherosclerosis group assigned to colchicine (105 [11.1%], 3.88 [95% CI, 3.21-4.70] per 100 person-years) versus usual care (132 [14.2%], 4.83 [4.07-5.73] per 100 person-years), which was not statistically significant (hazard ratio [HR], 0.83 [95% CI, 0.64-1.07]). There was no difference in the rate of the primary outcome according to treatment allocation in the nonatherosclerosis subgroup (HR, 0.94 [95% CI, 0.64-1.39]; <i>P</i>_interaction=0.60). There was a nonsignificant reduced risk of recurrent ischemic stroke in the colchicine arm (HR, 0.76 [95% CI, 0.56-1.05]) in the atherosclerosis group, but no difference in events was observed in the nonatherosclerotic group (HR, 0.92 [95% CI, 0.60-1.42]; <i>P</i>_interaction=0.48). In the prespecified on-treatment analysis, colchicine reduced the risk of MACE in patients with atherosclerosis (HR, 0.76 [95% CI, 0.58-0.99]) but not without (HR, 0.95 [95% CI, 0.63-1.42]; <i>P</i>_interaction=0.37).</p><p><strong>Conclusions: </strong>There were no significant between-group interactions for colchicine and atherosclerosis for MACE in intention-to-treat or on-treatment populations. However, outcome events were numerically fewer in patients with atherosclerosis assigned to colchicine, and significant benefit was observed in the on-treatment analysis in this group. Data suggest that the presence of atherosclerosis should be an inclusion criterion in future anti-inflammatory therapy trials.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT02898610.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":" ","pages":"2981-2990"},"PeriodicalIF":11.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune Checkpoint B7-H3 Inhibition Reprograms Acute Neuroinflammation and Protects the Brain After Acute Ischemic Stroke.","authors":"Arun Kumar Boda, Kit-Kay Mak, Weiguo Li, Bharath Chelluboina","doi":"10.1161/STROKEAHA.126.055713","DOIUrl":"10.1161/STROKEAHA.126.055713","url":null,"abstract":"<p><strong>Background: </strong>The role of immune checkpoint B7-H3 in acute ischemic stroke prognosis and poststroke immunosuppression remains uninvestigated, despite the clinical significance of immune checkpoints with inflammaging and poststroke infections. In this study, we investigated the effect of regulating cerebral induction of B7-H3 after acute ischemic stroke and evaluated its longitudinal impact on brain damage, neuroinflammation, vascular integrity, host defense gene regulation, and functional outcomes.</p><p><strong>Methods: </strong>C57BL/6 mice were subjected to transient middle cerebral artery occlusion and injected (intravenously) with either B7-H3 small interfering RNA or a negative (nontargeting) small interfering RNA at 5 minutes after reperfusion. On poststroke days 1, 3, and 7, magnetic resonance imaging of the mouse brain was performed using a 9.4-T scanner to assess brain damage (T2, apparent diffusion coefficient, and kurtosis) and blood-brain barrier integrity (T1 with contrast). Real-time quantitative polymerase chain reaction and NanoString nCounter neuroinflammation panels were used to determine acute changes in overall neuroinflammatory functions mediated by B7-H3. Motor function was assessed between days 1 and 7 of reperfusion.</p><p><strong>Results: </strong>Early inhibition of B7-H3 after stroke significantly reduced blood-brain barrier disruption and brain damage and promoted functional outcomes. Poststroke neuroinflammation was reprogrammed with B7-H3 inhibition to balance neuroprotective anti-inflammatory mechanisms without compromising the immune response, which is crucial for preventing poststroke infections.</p><p><strong>Conclusions: </strong>The longitudinal assessment of blood-brain barrier, infarction, and proinflammatory cytokines demonstrates that B7-H3 induction during the acute period after stroke mediates poststroke neuroinflammation and secondary brain damage.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":" ","pages":"3152-3158"},"PeriodicalIF":11.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13557181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"David G. Sherman Lecture: The Eternal Quest for Optimal Stroke Prevention.","authors":"Seemant Chaturvedi","doi":"10.1161/STROKEAHA.126.055573","DOIUrl":"10.1161/STROKEAHA.126.055573","url":null,"abstract":"<p><p>Despite decades of clinical trial activity in stroke prevention, critical gaps remain in the evidence base guiding management of symptomatic carotid and intracranial stenosis and the quality of anticoagulation care delivered to patients with atrial fibrillation (AF). This article synthesizes recent evidence and ongoing research efforts addressing 2 enduring challenges: demonstrating the value of intensive medical therapy relative to interventional approaches and improving the quality of stroke prevention care in AF. Previous trials focused on intracranial stenosis established that aggressive, protocol-driven medical management substantially reduces recurrent vascular events. In the realm of carotid stenosis, landmark trials conducted >3 decades ago no longer reflect modern pharmacological capabilities. Emerging evidence from plaque imaging, particularly intraplaque hemorrhage on magnetic resonance imaging, suggests that stenosis severity alone is an insufficient determinant of treatment strategy. Simultaneously, strokes related to AF continue to rise in the United States, driven by demographic aging, and large vessel occlusion strokes attributable to undertreated AF represent a preventable burden on the health system. Patient-centered, precision stroke prevention requires contemporary prospective data, integration of advanced vascular imaging biomarkers, and systematic improvements in preventative therapies for patients with AF. Targeting these areas holds promise for improving stroke prevention in the coming decades.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":"57 10","pages":"3195-3199"},"PeriodicalIF":11.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S-Nitrosylation of Endothelial FK506-Binding Protein 5 Impairs Angiogenesis via PHLPP-AKT Axis in Ischemic Stroke.","authors":"Xi-Yue Zhang, Hang Xu, Wei Guo, Hua-Lin Wang, Zhi-Hui Sun, Yan-Yan Liu, Han-Lian Xiao, Juan Ji, Xiu-Lan Sun","doi":"10.1161/STROKEAHA.126.056196","DOIUrl":"10.1161/STROKEAHA.126.056196","url":null,"abstract":"<p><strong>Background: </strong>Angiogenesis contributes to vascular repair and functional recovery after ischemic stroke, yet how nitric oxide-mediated S-nitrosylation shapes this response remains unclear. We investigated the role of S-nitrosylation in postischemic angiogenesis and the underlying molecular mechanism.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":21989,"journal":{"name":"Stroke","volume":" ","pages":"3106-3123"},"PeriodicalIF":11.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148841259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}