Evidence map›Paper›PMID 41293815›Full record

ArticleCirculation research2026

Circadian Control of Neutrophils Drives Collateral Perfusion and Stroke Outcome.

Sandra Vázquez-Reyes, Alicia García-Culebras, Gaohong Di, Francisco J De Castro-Millán, Blanca Díaz-Benito, Carmen Nieto-Vaquero, Alessandra Ruiz-Sanchez, Eneko Merino-Casamayor, Carlos Parra-Pérez, Ana Moraga and 16 more

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Article in Circulation research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

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0cells of the map it votes in

8citing papers in PubMed

–field-weighted citation impact

1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed.

Hyperacute Interleukin-1β Production and Neutrophil Extracellular Trap Formation in the Cerebral Circulation of Stroke Patients with Large Vessel Occlusion.Annals of neurology · 2026
Article
Exercise and Circadian Rhythm Regulation: Mechanisms, Resilience, and Therapeutic Potential for Neurological Diseases.CNS neuroscience & therapeutics · 2026
Review
Analytical Methods and Application of Single-Cell and Single-Nucleus Transcriptomics in the Study of Ischemic Stroke.Biomolecules · 2026
Review
Comprehensive Evaluation of YJ-2 as a PAD4 Inhibitor in Alleviating Ischemic Brain Injury: From NETs-Induced Neurotoxicity to In Vivo Neuroprotection.CNS neuroscience & therapeutics · 2026
Article
Neutrophil Heterogeneity: Molecules to Cellular Behavior.Life (Basel, Switzerland) · 2026
Review
Circadian control of immune homeostasis in cardiovascular health and disease.Frontiers in immunology · 2026
Review
Mediation of the relationship between cerebral blood flow and functional outcomes by quantification of perforator collateral capacity in patients with minor stroke and large vessel occlusion.Frontiers in neurology · 2026
Observational
Beyond the ischemic brain: Expanding single-cell transcriptomics in stroke research to extracentral nervous system systems, biological contexts, and poststroke complications.Brain circulation
Article

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

26 authors.

Sandra Vázquez-Reyes *Cardiovascular Risk Factors and Brain Function Programme (S.V.-R., A.G.-C., F.J.D.C.-M., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.R.-P., A.A.-C., I.B., M.I.C., M.A.M.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0000-0002-7365-975X

Alicia García-Culebras *Cardiovascular Risk Factors and Brain Function Programme (S.V.-R., A.G.-C., F.J.D.C.-M., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.R.-P., A.A.-C., I.B., M.I.C., M.A.M.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0000-0003-2362-0117

Gaohong Di *Unidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, (S.V.-R., A.G.-C., G.D., F.J.D.C.-M., B.D.-B., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.M., M.I.C., I.L., M.A.M.), Universidad Complutense de Madrid (UCM), Spain.

Francisco J De Castro-Millán *Cardiovascular Risk Factors and Brain Function Programme (S.V.-R., A.G.-C., F.J.D.C.-M., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.R.-P., A.A.-C., I.B., M.I.C., M.A.M.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

Blanca Díaz-BenitoUnidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, (S.V.-R., A.G.-C., G.D., F.J.D.C.-M., B.D.-B., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.M., M.I.C., I.L., M.A.M.), Universidad Complutense de Madrid (UCM), Spain.ORCID 0000-0002-9491-0616

Carmen Nieto-VaqueroCardiovascular Risk Factors and Brain Function Programme (S.V.-R., A.G.-C., F.J.D.C.-M., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.R.-P., A.A.-C., I.B., M.I.C., M.A.M.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0009-0002-1653-9943

Alessandra Ruiz-SanchezCardiovascular Risk Factors and Brain Function Programme (S.V.-R., A.G.-C., F.J.D.C.-M., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.R.-P., A.A.-C., I.B., M.I.C., M.A.M.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0009-0002-4867-690X

Eneko Merino-CasamayorCardiovascular Risk Factors and Brain Function Programme (S.V.-R., A.G.-C., F.J.D.C.-M., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.R.-P., A.A.-C., I.B., M.I.C., M.A.M.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0009-0002-8629-9949

Carlos Parra-PérezCardiovascular Risk Factors and Brain Function Programme (S.V.-R., A.G.-C., F.J.D.C.-M., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.R.-P., A.A.-C., I.B., M.I.C., M.A.M.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0009-0007-3817-1445

Ana MoragaUnidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, (S.V.-R., A.G.-C., G.D., F.J.D.C.-M., B.D.-B., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.M., M.I.C., I.L., M.A.M.), Universidad Complutense de Madrid (UCM), Spain.ORCID 0000-0001-6695-557X

César Core-BarreraEmergency Department, Hospital Universitario El Escorial, Madrid, Spain (C.C.-B.).

Patricia CallejaInstituto de Investigación Sanitaria Hospital 12 de Octubre (imas12, i+12), Madrid, Spain (B.D.-B., A.M., P.C., I.L.).ORCID 0000-0003-4858-1927

Ana DopazoGenomics Unit (A.D., S.C.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0000-0002-4910-1684

Sergio CallejasGenomics Unit (A.D., S.C.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0000-0003-3351-4940

Andrea Rubio-PonceCardiovascular Risk Factors and Brain Function Programme (S.V.-R., A.G.-C., F.J.D.C.-M., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.R.-P., A.A.-C., I.B., M.I.C., M.A.M.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0000-0002-4275-8835

Alejandra Aroca-CrevillénCardiovascular Risk Factors and Brain Function Programme (S.V.-R., A.G.-C., F.J.D.C.-M., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.R.-P., A.A.-C., I.B., M.I.C., M.A.M.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0000-0002-2481-0863

Fátima Sánchez-CaboBioinformatics Unit (F.S.-C., S.P.E.B., C.T.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0000-0003-1881-1664

Sara Pascual El BobakryBioinformatics Unit (F.S.-C., S.P.E.B., C.T.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0009-0009-1938-3236

Carlos TorrojaBioinformatics Unit (F.S.-C., S.P.E.B., C.T.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0000-0001-8914-3400

Elga EspositoRadiology Department, Massachusetts General Hospital, Harvard Medical School, Boston (E.E., E.H.L.).ORCID 0000-0002-8287-2747

Eng H LoRadiology Department, Massachusetts General Hospital, Harvard Medical School, Boston (E.E., E.H.L.).ORCID 0000-0002-9327-2915

Iván BallesterosCardiovascular Risk Factors and Brain Function Programme (S.V.-R., A.G.-C., F.J.D.C.-M., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.R.-P., A.A.-C., I.B., M.I.C., M.A.M.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

Andrés HidalgoCardiovascular Regeneration Programme (A.A.-C., A.H.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0000-0001-5513-555X

María Isabel CuarteroCardiovascular Risk Factors and Brain Function Programme (S.V.-R., A.G.-C., F.J.D.C.-M., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.R.-P., A.A.-C., I.B., M.I.C., M.A.M.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0000-0003-4728-068X

Ignacio LizasoainUnidad de Investigación Neurovascular, Departamento de Farmacología y Toxicología, Facultad de Medicina, (S.V.-R., A.G.-C., G.D., F.J.D.C.-M., B.D.-B., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.M., M.I.C., I.L., M.A.M.), Universidad Complutense de Madrid (UCM), Spain.ORCID 0000-0002-6028-7379

María Ángeles MoroCardiovascular Risk Factors and Brain Function Programme (S.V.-R., A.G.-C., F.J.D.C.-M., C.N.-V., A.R.-S., E.M.-C., C.P.-P., A.R.-P., A.A.-C., I.B., M.I.C., M.A.M.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.ORCID 0000-0003-1010-8237

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundStroke remains a leading cause of mortality and disability, driven by complex, time-dependent mechanisms that aggravate ischemic injury. Collateral perfusion dictates infarct size, expansion rate, and penumbral preservation, yet its regulation is poorly understood. Beyond structural/genetic factors such as aging or cardiovascular risk, functional influences like circadian immune activity may also affect vascular patency. Neutrophils, key mediators of ischemic injury, exhibit circadian oscillations in phenotype and function that could modulate collateral flow and stroke outcome.

methodsWe combined permanent and transient middle cerebral artery occlusion models in mice with flow cytometry, single-cell RNA sequencing, confocal microscopy, and laser speckle imaging to investigate time-of-day-dependent neutrophil mechanisms in stroke. Pharmacological (chloramidine, DNase-I) and genetic (Pad4 [peptidyl arginine deiminase 4]

resultsInfarct volume and neurological deficits exhibited clear circadian oscillations, with worse outcomes when stroke occurred during the murine inactive phase (Zeitgeber time 5) versus the active phase (Zeitgeber time 13). These fluctuations disappeared after neutrophil depletion or clock disruption. During the inactive phase, neutrophils displayed an activated, NET-prone phenotype, causing microvascular stalling and reduced collateral perfusion. Inhibiting NET formation pharmacologically or through Pad4 deletion restored perfusion and abolished time-of-day effects. In patients, neutrophil and NET-related biomarkers (MPO [myeloperoxidase], elastase, sCD40L [soluble CD40 ligand]) showed diurnal oscillations, peaking during the human inactive phase (evening/night), coinciding with reduced collateral flow and poorer outcomes.

conclusionsTime-of-day regulation of neutrophil function critically determines collateral perfusion and stroke severity. Neutrophil-driven NETosis during the inactive phase promotes microvascular obstruction and worsens outcomes. Targeting NET formation or timing therapy could enhance collateral efficacy and offer novel chronotherapeutic opportunities for stroke treatment.

Indexed as

Cerebrovascular CirculationCircadian RhythmCollateral CirculationInfarction, Middle Cerebral ArteryIschemic StrokeNeutrophilsStrokeAgedAnimalsARNTL Transcription FactorsDisease Models, AnimalExtracellular TrapsFemaleHumansMaleMiceARNTL Transcription FactorsBmal1 protein, mousepeptidylarginine deiminase 4, mouseProtein-Arginine Deiminase Type 4Receptors, CXCR4biomarkerscircadian rhythmneutrophilsperfusionstroke

Identifiers

PMID41293815

DOI10.1161/CIRCRESAHA.125.326438

PMCPMC12822775

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