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

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).

tPA Deficiency Underlies Neurovascular Coupling Dysfunction by Amyloid-β

“…Tissue plasminogen activator (tPA) is a serine protease best known for its role in intravascular fibrinolysis, glutamate neurotransmission, and synaptic plasticity (Baranes et al, 1998;Benchenane et al, 2004;Samson and Medcalf, 2006;Diaz et al, 2019). In addition, tPA is required for the full expression of functional hyperemia (Park et al, 2008a;Iadecola, 2017;Anfray et al, 2020). Mice lacking tPA have a marked attenuation in the increase in CBF induced by neural activity, resulting from reduced production of nitric oxide (NO) during the activation of NMDA receptors (NMDARs), one of the drivers of function hyperemia (Park et al, 2008a;Iadecola, 2017).…”

Variants of WNT7A and GPR124 are associated with hemorrhagic transformation following intravenous thrombolysis in ischemic stroke

“…However, the pathogenesis of HT remains unclear and no reliable indicators can predict HT occurrence, which have been profoundly limiting the application of rt‐PA to AIS patients. BBB disruption is reported numerously by many groups following reperfusion therapy in both animal stroke models and AIS patients and is shown to be a major contributing factor of HT 7,17‐20,23,49 . The essential role of cerebrovascular Wnt/β‐catenin signaling in BBB formation and integrity has been well documented by us and others in animal studies.…”

Megalencephalic leukoencephalopathy with subcortical cysts is a developmental disorder of the gliovascular unit

“…In the hippocampal stratum radiatum, GFAP-positive astrocytic processes are normally polarized perpendicular to the pyramidal cell layer (PL) [40]. We evaluated this preferential orientation and measured the polarity index, which corresponds to the ratio between parallel (axial) and perpendicular (lateral) crossing points between GFAP-positive processes and a grid oriented with the PL (Fig.…”

“…MLC1 expression is a progressive process that starts in the mouse at P5 and completes at P15 [16]. In contrast, astrocyte ramification in the stratum radiatum increases greatly between P8 and P16 [40]. We therefore wondered whether the morphological and polarity defects observed in adult Mlc1 KO astrocytes might be caused by an impairment development.…”

“…We therefore wondered whether the morphological and polarity defects observed in adult Mlc1 KO astrocytes might be caused by an impairment development. Hence, we analyzed the morphology and orientation of GFAP-immunolabeled astrocytic processes on P10 and P15 [40] (Fig. 8; Table S8).…”