Blood tPA of liver origin contributes to neurovascular coupling involving brain endothelial NMDA receptors

Abstract Regulation of the cerebral blood flow (CBF) involves complex mechanisms with direct influences on brain functions and dysfunctions. Among these mechanisms it was proposed that the serine protease tissue-type plasminogen activator (tPA) could play a role in the control of neurovascular coupling (NVC) induced by whiskers stimulation in rodents through its action on N-methyl-D-Aspartate receptors (NMDARs). In the present study, using tPANull mice, conditional deletions of either endothelial tPA (VECad-CreΔtPA) or endothelial NMDARs GluN1 subunit (VECad-CreΔGluN1), parabioses between wild-type and tPANull mice, hydrodynamic transfections-induced deletion of liver tPA, hepatectomy and pharmacological approaches in mice, we have unveiled this mechanism in detail. We thus demonstrate that physiological concentrations of vascular tPA, produced and released by the liver endothelial cells in a bradykinin type 2 receptors-dependent manner, promotes NVC, by a mechanism dependent of brain endothelial NMDA receptors. These data highlight a new mechanism of the regulation of NVC involving both endothelial tPA and NMDA receptors.