Blood Tissue Plasminogen Activator (tPA) of Liver Origin Contributes to Neurovascular Coupling Involving Brain Endothelial N-Methyl-D-Aspartate (NMDA) Receptors

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 tPA mice, conditional deletions of either endothelial tPA (VECad-Cre) or endothelial GluN1 subunit of NMDARs (VECad-Cre), parabioses between wild-type and tPA 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.