Key role of tissue plasminogen activator in neurovascular coupling

Abstract

The increase in blood flow evoked by synaptic activity is essential for normal brain function and underlies functional brain imaging signals. Nitric oxide, a vasodilator released by NMDA receptor activation, is critical for the flow increase, but the factors linking NMDA receptor activity to nitric oxide-dependent hyperemia are poorly understood. Here, we show that tissue plasminogen activator (tPA), a serine protease implicated in NMDA receptor signaling, is required for the flow increase evoked by somatosensory stimulation. tPA acts by facilitating neuronal nitric oxide release, but this effect does not involve enhancement of NMDA currents or the associated intracellular Ca 2؉ rise. Rather, the evidence suggests that tPA controls NMDA-dependent nitric oxide synthesis by influencing the phosphorylation state of neuronal nitric oxide synthase. These findings unveil a previously unrecognized role of tPA in vital homeostatic mechanisms coupling NMDA receptor signaling with nitric oxide synthesis and local cerebral perfusion.calcium ͉ cerebral blood flow ͉ mouse ͉ nitric oxide ͉ phosphorylation T issue plasminogen activator (tPA) is a serine protease best known for its role in intravascular fibrinolysis (1-3). tPA converts plasminogen (plg) into plasmin, a protease that cleaves fibrin and dissolves newly formed clots (2). The ''clot-busting'' properties of tPA have been used successfully in the treatment of myocardial infarction and ischemic stroke (4, 5). In addition to its role in fibrinolysis, tPA has recently emerged as a pleiotropic neuromodulator implicated in various aspects of brain function (6). tPA is stored in neurons and is released in an activity-dependent manner via exocytosis (7,8). tPA is involved in neurotransmission, synaptic plasticity, dendritic remodeling, and sympathetic nerve activity, effects related to its ability to influence NMDA receptor function, extracellular matrix integrity, and neurotransmitter release (9-15). In addition, tPA released from endothelial cells modulates cerebrovascular tone and may contribute to the hemodynamic changes induced by brain ischemia and trauma (3,(16)(17)(18).The vascular effects of tPA and its involvement in synaptic function raise the possibility that this protease also contributes to the neurovascular mechanisms linking brain activity to cerebral blood flow (CBF). The brain lacks energy reserves and its integrity depends on a continuous supply of oxygen and glucose through CBF (19). Because of such dependence on CBF, the brain is endowed with complex regulatory mechanisms that match local cerebral perfusion to the energy needs of active neurons on a moment-to-moment basis (19). Thus, an increase in regional brain activity is associated with a rapid and spatially focused increase in CBF, a response termed ''functional hyperemia' ' (19, 20). The close temporal and spatial correspondence between brain activity and CBF constitutes the basis of functional brain imaging techniques that use the local hemodynamic response evoked by neural activity to localize b...

IGF‐1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging

“…The signal was amplified with an AC/DC differential amplifier (high pass at 1 Hz, low pass at 1 kHz) (Model 3000; A‐M Systems, Inc. Carlsborg, WA, USA) and digitalized by the PowerLab/Labchart data acquisition system (ADInstruments, Colorado Springs, CO, USA) with a sampling rate of 40 kHz. Basal activity was analyzed as distribution of wave amplitude as a function of frequency (Park et al ., 2008), and the negative amplitude in the somatosensory evoked field potential response was considered as the excitatory postsynaptic potential (fEPSP) (Lind et al ., 2013). Analyses were performed on the average of 10 stimulation trials.…”

tPA-S481A Prevents Impairment of Cerebrovascular Autoregulation by Endogenous tPA after Traumatic Brain Injury by Upregulating p38 MAPK and Inhibiting ET-1

“…8 More recently, it was observed that tPA is critical for the full expression of the flow increase evoked by activation of the mouse whisker barrel cortex. 29 Specifically, tPA promoted nitric oxide (NO) synthesis during NMDA-R activation by modulating phosphorylation of nNOS. 29 These findings suggest that tPA is a key factor linking NMDA-R activation to NO synthesis and functional hyperemia.…”

“…29 Specifically, tPA promoted nitric oxide (NO) synthesis during NMDA-R activation by modulating phosphorylation of nNOS. 29 These findings suggest that tPA is a key factor linking NMDA-R activation to NO synthesis and functional hyperemia.…”

Glucagon Protects Against Impaired NMDA-Mediated Cerebrovasodilation and Cerebral Autoregulation during Hypotension after Brain Injury by Activating cAMP Protein Kinase A and Inhibiting Upregulation of tPA

“…More recently it was observed that tPA is critical for the full expression of the flow increase evoked by activation of the mouse whisker barrel cortex (Park et al, 2008). Specifically, tPA promoted NO synthesis during NMDA receptor activation by modulating phosphorylation of nNOS (Park et al, 2008).…”