Blood tissue Plasminogen Activator (tPA) of liver origin contributes to neurovascular coupling involving brain endothelial N-Methyl-D-Aspartate (NMDA) receptors

Author:

Furon Jonathane,Yetim Mervé,Pouettre Elsa,Martinez de Lizarrondo Sara,Maubert Eric,Hommet Yannick,Lebouvier Laurent,Zheng Ze,Ali Carine,Vivien Denis

Abstract

Abstract Background Regulation of cerebral blood flow (CBF) directly influence brain functions and dysfunctions and involves complex mechanisms, including neurovascular coupling (NVC). It was suggested that the serine protease tissue-type plasminogen activator (tPA) could control CNV induced by whisker stimulation in rodents, through its action on N-methyl-d-Aspartate receptors (NMDARs). However, the origin of tPA and the location and mechanism of its action on NMDARs in relation to CNV remained debated. Methods Here, we answered these issues using tPANull mice, conditional deletions of either endothelial tPA (VECad-CreΔtPA) or endothelial GluN1 subunit of NMDARs (VECad-CreΔGluN1), parabioses between wild-type and tPANull mice, hydrodynamic transfection-induced deletion of liver tPA, hepatectomy and pharmacological approaches. Results We thus demonstrate that physiological concentrations of vascular tPA, achieved by the bradykinin type 2 receptors-dependent production and release of tPA from liver endothelial cells, promote NVC, through a mechanism dependent on brain endothelial NMDARs. Conclusions These data highlight a new mechanism of regulation of NVC involving both endothelial tPA and NMDARs.

Publisher

Springer Science and Business Media LLC

Subject

Cellular and Molecular Neuroscience,Developmental Neuroscience,Neurology,General Medicine

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