Circulating tPA contributes to neurovascular coupling by a mechanism involving the endothelial NMDA receptors

Author:

Anfray Antoine1,Drieu Antoine1,Hingot Vincent2,Hommet Yannick1,Yetim Mervé1,Rubio Marina1,Deffieux Thomas2,Tanter Mickael2,Orset Cyrille1,Vivien Denis13

Affiliation:

1. Normandie University, UNICAEN, INSERM, UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Caen, France

2. Institut Langevin, CNRS, INSERM, ESPCI Paris, PSL Research University, Paris, France

3. CHU Caen, Department of Clinical Research, Caen Normandie University Hospital, Avenue de la Côte de Nacre, Caen, France

Abstract

The increase of cerebral blood flow evoked by neuronal activity is essential to ensure enough energy supply to the brain. In the neurovascular unit, endothelial cells are ideally placed to regulate key neurovascular functions of the brain. Nevertheless, some outstanding questions remain about their exact role neurovascular coupling (NVC). Here, we postulated that the tissue-type plasminogen activator (tPA) present in the circulation might contribute to NVC by a mechanism dependent of its interaction with endothelial N-Methyl-D-Aspartate Receptor (NMDAR). To address this question, we used pharmacological and genetic approaches to interfere with vascular tPA-dependent NMDAR signaling, combined with laser speckle flowmetry, intravital microscopy and ultrafast functional ultrasound in vivo imaging. We found that the tPA present in the blood circulation is capable of potentiating the cerebral blood flow increase induced by the activation of the mouse somatosensorial cortex, and that this effect is mediated by a tPA-dependent activation of NMDAR expressed at the luminal part of endothelial cells of arteries. Although blood molecules, such as acetylcholine, bradykinin or ATP are known to regulate vascular tone and induce vessel dilation, our present data provide the first evidence that circulating tPA is capable of influencing neurovascular coupling (NVC).

Publisher

SAGE Publications

Subject

Cardiology and Cardiovascular Medicine,Clinical Neurology,Neurology

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