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

BackgroundRegulation 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.MethodsHere, we answered these issues using tPA(Null) mice, conditional deletions of either endothelial tPA (VECad-Cre(Delta tPA)) or endothelial GluN1 subunit of NMDARs (VECad-Cre(Delta GluN1)), parabioses between wild-type and tPA(Null) mice, hydrodynamic transfection-induced deletion of liver tPA, hepatectomy and pharmacological approaches.ResultsWe 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.ConclusionsThese data highlight a new mechanism of regulation of NVC involving both endothelial tPA and NMDARs.

Automated summary

This study reveals a new mechanism of regulation of neurovascular coupling (NVC) by demonstrating the role of tPA and NMDARs.