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Parabiosis Discriminates the Circulating, Endothelial, and Parenchymal Contributions of Endogenous Tissue-Type Plasminogen Activator to Stroke.
Furon, Jonathane; Lebrun, Florent; Yétim, Mervé; Levard, Damien; Marie, Pauline; Orset, Cyrille; Martinez de Lizarrondo, Sara; Vivien, Denis; Ali, Carine.
Afiliación
  • Furon J; Normandie University, UNICAEN, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, Groupement d'Intérêt Public (GIP) Cyceron, Institut Blood and Brain @ Caen-Normandie, Caen, France (J.F., F.L., M.Y., D.L., P.M., C.O., S.M.d.L., D.V., C.A.).
  • Lebrun F; Normandie University, UNICAEN, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, Groupement d'Intérêt Public (GIP) Cyceron, Institut Blood and Brain @ Caen-Normandie, Caen, France (J.F., F.L., M.Y., D.L., P.M., C.O., S.M.d.L., D.V., C.A.).
  • Yétim M; Normandie University, UNICAEN, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, Groupement d'Intérêt Public (GIP) Cyceron, Institut Blood and Brain @ Caen-Normandie, Caen, France (J.F., F.L., M.Y., D.L., P.M., C.O., S.M.d.L., D.V., C.A.).
  • Levard D; Normandie University, UNICAEN, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, Groupement d'Intérêt Public (GIP) Cyceron, Institut Blood and Brain @ Caen-Normandie, Caen, France (J.F., F.L., M.Y., D.L., P.M., C.O., S.M.d.L., D.V., C.A.).
  • Marie P; Department of Clinical Research, Caen-Normandie University Hospital, Centre Hospitalier Universitaire (CHU), France (D.V.).
  • Orset C; Normandie University, UNICAEN, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, Groupement d'Intérêt Public (GIP) Cyceron, Institut Blood and Brain @ Caen-Normandie, Caen, France (J.F., F.L., M.Y., D.L., P.M., C.O., S.M.d.L., D.V., C.A.).
  • Martinez de Lizarrondo S; Normandie University, UNICAEN, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, Groupement d'Intérêt Public (GIP) Cyceron, Institut Blood and Brain @ Caen-Normandie, Caen, France (J.F., F.L., M.Y., D.L., P.M., C.O., S.M.d.L., D.V., C.A.).
  • Vivien D; Normandie University, UNICAEN, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, Groupement d'Intérêt Public (GIP) Cyceron, Institut Blood and Brain @ Caen-Normandie, Caen, France (J.F., F.L., M.Y., D.L., P.M., C.O., S.M.d.L., D.V., C.A.).
  • Ali C; Normandie University, UNICAEN, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders, Groupement d'Intérêt Public (GIP) Cyceron, Institut Blood and Brain @ Caen-Normandie, Caen, France (J.F., F.L., M.Y., D.L., P.M., C.O., S.M.d.L., D.V., C.A.).
Stroke ; 55(3): 747-756, 2024 Mar.
Article en En | MEDLINE | ID: mdl-38288607
ABSTRACT

BACKGROUND:

Intravenous injection of alteplase, a recombinant tPA (tissue-type plasminogen activator) as a thrombolytic agent has revolutionized ischemic stroke management. However, tPA is a more complex enzyme than expected, being for instance able to promote thrombolysis, but at the same time, also able to influence neuronal survival and to affect the integrity of the blood-brain barrier. Accordingly, the respective impact of endogenous tPA expressed/present in the brain parenchyma versus in the circulation during stroke remains debated.

METHODS:

To address this issue, we used mice with constitutive deletion of tPA (tPANull [tPA-deficient mice]) or conditional deletion of endothelial tPA (VECad [vascular endothelial-Cadherin-Cre-recombinase]-Cre∆tPA). We also developed parabioses between tPANull and wild-type mice (tPAWT), anticipating that a tPAWT donor would restore levels of tPA to normal ones, in the circulation but not in the brain parenchyma of a tPANull recipient. Stroke outcomes were investigated by magnetic resonance imaging in a thrombo-embolic or a thrombotic stroke model, induced by local thrombin injection or FeCl3 application on the endothelium, respectively.

RESULTS:

First, our data show that endothelial tPA, released into the circulation after stroke onset, plays an overall beneficial role following thrombo-embolic stroke. Accordingly, after 24 hours, tPANull/tPANull parabionts displayed less spontaneous recanalization and reperfusion and larger infarcts compared with tPAWT/tPAWT littermates. However, when associated to tPAWT littermates, tPANull mice had similar perfusion deficits, but less severe brain infarcts. In the thrombotic stroke model, homo- and hetero-typic parabionts did not differ in the extent of brain damages and did not differentially recanalize and reperfuse.

CONCLUSIONS:

Together, our data reveal that during thromboembolic stroke, endogenous circulating tPA from endothelial cells sustains a spontaneous recanalization and reperfusion of the tissue, thus, limiting the extension of ischemic lesions. In this context, the impact of endogenous parenchymal tPA is limited.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Accidente Cerebrovascular / Accidente Cerebrovascular Trombótico Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Stroke Año: 2024 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Accidente Cerebrovascular / Accidente Cerebrovascular Trombótico Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Stroke Año: 2024 Tipo del documento: Article