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Mark Nelson - One of the best experts on this subject based on the ideXlab platform.
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TRPV4 channels stimulate Ca2+-induced Ca2+ release in astrocytic endfeet and amplify Neurovascular Coupling responses
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Kathryn M. Dunn, David C. Hill-eubanks, Wolfgang Liedtke, Mark NelsonAbstract:In the CNS, astrocytes are sensory and regulatory hubs that play important roles in cerebral homeostatic processes, including matching local cerebral blood flow to neuronal metabolism (Neurovascular Coupling). These cells possess a highly branched network of processes that project from the soma to neuronal synapses as well as to arterioles and capillaries, where they terminate in “endfeet” that encase the blood vessels. Ca2+ signaling within the endfoot mediates Neurovascular Coupling; thus, these functional microdomains control vascular tone and local perfusion in the brain. Transient receptor potential vanilloid 4 (TRPV4) channels—nonselective cation channels with considerable Ca2+ conductance—have been identified in astrocytes, but their function is largely unknown. We sought to characterize the influence of TRPV4 channels on Ca2+ dynamics in the astrocytic endfoot microdomain and assess their role in Neurovascular Coupling. We identified local TRPV4-mediated Ca2+ oscillations in endfeet and further found that TRPV4 Ca2+ signals are amplified and propagated by Ca2+-induced Ca2+ release from inositol trisphosphate receptors (IP3Rs). Moreover, TRPV4-mediated Ca2+ influx contributes to the endfoot Ca2+ response to neuronal activation, enhancing the accompanying vasodilation. Our results identify a dynamic synergy between TRPV4 channels and IP3Rs in astrocyte endfeet and demonstrate that TRPV4 channels are engaged in and contribute to Neurovascular Coupling.
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Intermediate‐conductance calcium‐activated potassium channels participate in Neurovascular Coupling
British journal of pharmacology, 2011Co-Authors: Thomas A Longden, Kathryn M. Dunn, Henning J. Draheim, Mark Nelson, Arthur H. Weston, Gillian EdwardsAbstract:BACKGROUND AND PURPOSE Controlling vascular tone involves K+ efflux through endothelial cell small- and intermediate-conductance calcium-activated potassium channels (KCa2.3 and KCa3.1, respectively). We investigated the expression of these channels in astrocytes and the possibility that, by a similar mechanism, they might contribute to Neurovascular Coupling. EXPERIMENTAL APPROACH Transgenic mice expressing enhanced green fluorescent protein (eGFP) in astrocytes were used to assess KCa2.3 and KCa3.1 expression by immunohistochemistry and RT-PCR. KCa currents in eGFP-positive astrocytes were determined in situ using whole-cell patch clamp electrophysiology. The contribution of KCa3.1 to Neurovascular Coupling was investigated in pharmacological experiments using electrical field stimulation (EFS) to evoke parenchymal arteriole dilatation in FVB/NJ mouse brain slices and whisker stimulation to evoke changes in cerebral blood flow in vivo, measured by laser Doppler flowmetry. KEY RESULTS KCa3.1 immunoreactivity was restricted to astrocyte processes and endfeet and RT-PCR confirmed astrocytic KCa2.3 and KCa3.1 mRNA expression. With 200 nM [Ca2+]i, the KCa2.1-2.3/KCa3.1 opener NS309 increased whole-cell currents. CyPPA, a KCa2.2/KCa2.3 opener, was without effect. With 1 µM [Ca2+]i, the KCa3.1 inhibitor TRAM-34 reduced currents whereas apamin (KCa2.1-2.3 blocker) had no effect. CyPPA also inhibited currents evoked by NS309 in HEK293 cells expressing KCa3.1. EFS-evoked Fluo-4 fluorescence confirmed astrocyte endfoot recruitment into Neurovascular Coupling. TRAM-34 inhibited EFS-evoked arteriolar dilatation by 50% whereas charybdotoxin, a blocker of KCa3.1 and the large-conductance KCa channel, KCa1.1, inhibited dilatation by 82%. TRAM-34 reduced the cortical hyperaemic response to whisker stimulation by 40%. CONCLUSION AND IMPLICATIONS Astrocytes express functional KCa3.1 channels, and these contribute to Neurovascular Coupling. LINKED ARTICLES This article is part of a themed issue on Vascular Endothelium in Health and Disease. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-3
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Potassium channels and Neurovascular Coupling.
Circulation journal : official journal of the Japanese Circulation Society, 2010Co-Authors: Kathryn M. Dunn, Mark NelsonAbstract:Neuronal activity is communicated to the cerebral vasculature so that adequate perfusion of brain tissue is maintained at all levels of neuronal metabolism. An increase in neuronal activity is accompanied by vasodilation and an increase in local cerebral blood flow. This process, known as Neurovascular Coupling (NVC) or functional hyperemia, is essential for cerebral homeostasis and survival. Neuronal activity is encoded in astrocytic Ca(2+) signals that travel to astrocytic processes (;endfeet') encasing parenchymal arterioles within the brain. Astrocytic Ca(2+) signals cause the release of vasoactive substances to cause relaxation, and in some circumstances contraction, of the smooth muscle cells (SMCs) of parenchymal arterioles to modulate local cerebral blood flow. Activation of potassium channels in the SMCs has been proposed to mediate NVC. Here, the current state of knowledge of NVC and potassium channels in parenchymal arterioles is reviewed.
George C. Wellman - One of the best experts on this subject based on the ideXlab platform.
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Inversion of Neurovascular Coupling after subarachnoid hemorrhage in vivo
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2017Co-Authors: Matilde Balbi, Masayo Koide, George C. Wellman, Nikolaus PlesnilaAbstract:Subarachnoid hemorrhage (SAH) induces acute changes in the cerebral microcirculation. Recent findings ex vivo suggest Neurovascular Coupling (NVC), the process that increases cerebral blood flow up...
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Purinergic signaling triggers endfoot high-amplitude Ca2+ signals and causes inversion of Neurovascular Coupling after subarachnoid hemorrhage.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2016Co-Authors: Anthony Pappas, Masayo Koide, George C. WellmanAbstract:Neurovascular Coupling supports brain metabolism by matching focal increases in neuronal activity with local arteriolar dilation. Previously, we demonstrated that an emergence of spontaneous endfoot high-amplitude Ca2+ signals (eHACSs) caused a pathologic shift in Neurovascular Coupling from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage model animals. Extracellular purine nucleotides (e.g., ATP) can trigger astrocyte Ca2+ oscillations and may be elevated following subarachnoid hemorrhage. Here, the role of purinergic signaling in subarachnoid hemorrhage-induced eHACSs and inversion of Neurovascular Coupling was examined by imaging parenchymal arteriolar diameter and astrocyte Ca2+ signals in rat brain slices using two-photon fluorescent and infrared-differential interference contrast microscopy. We report that broad-spectrum inhibition of purinergic (P2) receptors using suramin blocked eHACSs and restored vasodilatory Neurovascular Coupling after subarachnoid hemorrhage. Importantly, eHACSs were also abolished using a cocktail of inhibitors targeting Gq-coupled P2Y receptors. Further, activation of P2Y receptors in brain slices from un-operated animals triggered high-amplitude Ca2+ events resembling eHACSs and disrupted Neurovascular Coupling. Neither tetrodotoxin nor bafilomycin A1 affected eHACSs suggesting that purine nucleotides are not released by ongoing neurotransmission and/or vesicular release after subarachnoid hemorrhage. These results indicate that purinergic signaling via P2Y receptors contributes to subarachnoid hemorrhage-induced eHACSs and inversion of Neurovascular Coupling.
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Activation of TRPV4 channels does not mediate inversion of Neurovascular Coupling after SAH.
Acta neurochirurgica. Supplement, 2014Co-Authors: Masayo Koide, George C. WellmanAbstract:Neurovascular Coupling (NVC) allows increased blood flow to metabolically active neurons and involves the Ca2+-dependent release of vasodilator influences by astrocyte endfeet that encase parenchymal arterioles. We previously reported inversion of NVC from dilation to constriction in brain slices from subarachnoid hemorrhage (SAH) model rats. Corresponding to NVC inversion, there was a marked increase in the amplitude of spontaneous Ca2+ oscillations in astrocyte endfeet. Calcium-permeable transient receptor potential vanilloid (TRPV)-4 channels have been reported in astrocyte endfeet, and activators of these channels enhance Ca2+ oscillations in healthy animals. Here, we examined the role of TRPV4 channels in the development of high-amplitude spontaneous Ca2+ oscillations in astrocyte endfeet and the inversion of Neurovascular Coupling after SAH. Treatment of brain slices with the TRPV4 channel antagonist, HC-067047 (10 μM), did not alter the amplitude of spontaneous Ca2+ oscillations after SAH. In addition, HC-067047 did not inhibit or change SAH-induced inversion of Neurovascular Coupling. In summary, TRPV4 channels do not appear to be involved in the inversion of Neurovascular Coupling after SAH. Further studies examining the impact of SAH on additional Ca2+ signaling pathways in astrocytes are likely to reveal valuable insights into new therapeutic strategies to advance SAH treatments.
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Subarachnoid Hemorrhage, Spreading Depolarizations and Impaired Neurovascular Coupling
Stroke research and treatment, 2013Co-Authors: Masayo Koide, Inna Sukhotinsky, Cenk Ayata, George C. WellmanAbstract:Aneurysmal subarachnoid hemorrhage (SAH) has devastating consequences on brain function including profound effects on communication between neurons and the vasculature leading to cerebral ischemia. Physiologically, Neurovascular Coupling represents a focal increase in cerebral blood flow to meet increased metabolic demand of neurons within active regions of the brain. Neurovascular Coupling is an ongoing process involving coordinated activity of the Neurovascular unit—neurons, astrocytes, and parenchymal arterioles. Neuronal activity can also influence cerebral blood flow on a larger scale. Spreading depolarizations (SD) are self-propagating waves of neuronal depolarization and are observed during migraine, traumatic brain injury, and stroke. Typically, SD is associated with increased cerebral blood flow. Emerging evidence indicates that SAH causes inversion of Neurovascular communication on both the local and global level. In contrast to other events causing SD, SAH-induced SD decreases rather than increases cerebral blood flow. Further, at the level of the Neurovascular unit, SAH causes an inversion of Neurovascular Coupling from vasodilation to vasoconstriction. Global ischemia can also adversely affect the Neurovascular response. Here, we summarize current knowledge regarding the impact of SAH and global ischemia on Neurovascular communication. A mechanistic understanding of these events should provide novel strategies to treat these Neurovascular disorders.
Rui M. Barbosa - One of the best experts on this subject based on the ideXlab platform.
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Neurovascular Coupling mediated by neuronal nitric oxide in hippocampus and the redox cycle of ascorbate and nitrite
Free Radical Biology and Medicine, 2018Co-Authors: João Laranjinha, Cátia F. Lourenço, Nuno R. Ferreira, Rui M. BarbosaAbstract:Neurovascular Coupling is critical for neuronal integrity and survival as it orchestrates the rapid and transient delivery of bioenergetic substrates by the local vasculature to neighboring cells, according to energy demands imposed by neural activation. Failure in Neurovascular Coupling, either during aging and disease (Alzheimer´s disease, AD) or following acute hypoxic conditions, compromises brain integrity and functionality. The regulation of Neurovascular Coupling is under the concerted cooperation of the cells comprising the Neurovascular unit. However, the complementary task of identifying modulators of NO activity on Neurovascular Coupling has remained largely underappreciated. We have come to conjecture that the redox and functional interplay of nitric oxide with ascorbate and nitrite would modulate the functionality of glutamatergic synapses in terms of Neurovascular Coupling. By using a multimodal approach to probe the dynamics of NO, ascorbate and cerebral blood flow in vivo in hippocampus of Wistar and Fisher 344 rats and of a triple transgenic mice model of AD we support that (1) neuronal-derived NO acts as a direct mediator of Neurovascular Coupling, (2) upon glutamatergic stimulation, volume signaling by NO is an intrinsically controlled mechanism due to increased blood flow, (3) Neurovascular Coupling is impaired in AD and aging due to vascular dysfunction, (4) under acidic/hypoxic conditions, nitrite is reduced by ascorbate to NO and (5) the redox interaction of nitrite/ascorbate/NO contributes to Neurovascular Coupling. Given that nitrite increases NO bioavailability and augments cerebral blood flow in hippocampus one may envisage that dietary nitrate via the nitrate:nitrite:NO pathway may help sustaining Neurovascular Coupling in aging and disease.
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Regulation of Neurovascular Coupling in the brain by nitrite
Free Radical Biology and Medicine, 2017Co-Authors: João Laranjinha, Cátia Marques, Ana Ledo, Cândida Dias, Nuno Ferreira, Rui M. BarbosaAbstract:The functional connection of glutamate receptors with nNOS in neurons contributes to the Coupling between neuronal activation and changes in local cerebral blood flow, i.e., the Neurovascular Coupling. Failure in Neurovascular Coupling, either during aging and disease (Alzheimer´s disease, AD) or following acute hypoxic conditions, compromises brain integrity and functionality. Hypoxia may compromise the Coupling by mechanisms that include a deficient synthesis of NO, for which O2 is a substrate. By using a multimodal approach to probe the dynamics of NO, ascorbate and cerebral blood flow in vivo in hippocampus of Wistar and Fisher 344 rats and of a triple transgenic mice model of AD we support that (1) neuronal-derived NO acts as a direct mediator of Neurovascular Coupling, (2) upon glutamatergic stimulation, volume signaling by NO is an intrinsically controlled mechanism due to increased blood flow, (3) Neurovascular Coupling is impaired in AD and aging due to vascular dysfunction, (4) under acidic/hypoxic conditions, nitrite is reduced by ascorbate to NO and (5) the redox interaction of nitrite/ascorbate/NO contributes to Neurovascular Coupling. The results support that dietary nitrate might modulate Neurovascular Coupling in aging and disease via the nitrate:nitrite:NO pathway.
Kathryn M. Dunn - One of the best experts on this subject based on the ideXlab platform.
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TRPV4 channels stimulate Ca2+-induced Ca2+ release in astrocytic endfeet and amplify Neurovascular Coupling responses
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Kathryn M. Dunn, David C. Hill-eubanks, Wolfgang Liedtke, Mark NelsonAbstract:In the CNS, astrocytes are sensory and regulatory hubs that play important roles in cerebral homeostatic processes, including matching local cerebral blood flow to neuronal metabolism (Neurovascular Coupling). These cells possess a highly branched network of processes that project from the soma to neuronal synapses as well as to arterioles and capillaries, where they terminate in “endfeet” that encase the blood vessels. Ca2+ signaling within the endfoot mediates Neurovascular Coupling; thus, these functional microdomains control vascular tone and local perfusion in the brain. Transient receptor potential vanilloid 4 (TRPV4) channels—nonselective cation channels with considerable Ca2+ conductance—have been identified in astrocytes, but their function is largely unknown. We sought to characterize the influence of TRPV4 channels on Ca2+ dynamics in the astrocytic endfoot microdomain and assess their role in Neurovascular Coupling. We identified local TRPV4-mediated Ca2+ oscillations in endfeet and further found that TRPV4 Ca2+ signals are amplified and propagated by Ca2+-induced Ca2+ release from inositol trisphosphate receptors (IP3Rs). Moreover, TRPV4-mediated Ca2+ influx contributes to the endfoot Ca2+ response to neuronal activation, enhancing the accompanying vasodilation. Our results identify a dynamic synergy between TRPV4 channels and IP3Rs in astrocyte endfeet and demonstrate that TRPV4 channels are engaged in and contribute to Neurovascular Coupling.
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Intermediate‐conductance calcium‐activated potassium channels participate in Neurovascular Coupling
British journal of pharmacology, 2011Co-Authors: Thomas A Longden, Kathryn M. Dunn, Henning J. Draheim, Mark Nelson, Arthur H. Weston, Gillian EdwardsAbstract:BACKGROUND AND PURPOSE Controlling vascular tone involves K+ efflux through endothelial cell small- and intermediate-conductance calcium-activated potassium channels (KCa2.3 and KCa3.1, respectively). We investigated the expression of these channels in astrocytes and the possibility that, by a similar mechanism, they might contribute to Neurovascular Coupling. EXPERIMENTAL APPROACH Transgenic mice expressing enhanced green fluorescent protein (eGFP) in astrocytes were used to assess KCa2.3 and KCa3.1 expression by immunohistochemistry and RT-PCR. KCa currents in eGFP-positive astrocytes were determined in situ using whole-cell patch clamp electrophysiology. The contribution of KCa3.1 to Neurovascular Coupling was investigated in pharmacological experiments using electrical field stimulation (EFS) to evoke parenchymal arteriole dilatation in FVB/NJ mouse brain slices and whisker stimulation to evoke changes in cerebral blood flow in vivo, measured by laser Doppler flowmetry. KEY RESULTS KCa3.1 immunoreactivity was restricted to astrocyte processes and endfeet and RT-PCR confirmed astrocytic KCa2.3 and KCa3.1 mRNA expression. With 200 nM [Ca2+]i, the KCa2.1-2.3/KCa3.1 opener NS309 increased whole-cell currents. CyPPA, a KCa2.2/KCa2.3 opener, was without effect. With 1 µM [Ca2+]i, the KCa3.1 inhibitor TRAM-34 reduced currents whereas apamin (KCa2.1-2.3 blocker) had no effect. CyPPA also inhibited currents evoked by NS309 in HEK293 cells expressing KCa3.1. EFS-evoked Fluo-4 fluorescence confirmed astrocyte endfoot recruitment into Neurovascular Coupling. TRAM-34 inhibited EFS-evoked arteriolar dilatation by 50% whereas charybdotoxin, a blocker of KCa3.1 and the large-conductance KCa channel, KCa1.1, inhibited dilatation by 82%. TRAM-34 reduced the cortical hyperaemic response to whisker stimulation by 40%. CONCLUSION AND IMPLICATIONS Astrocytes express functional KCa3.1 channels, and these contribute to Neurovascular Coupling. LINKED ARTICLES This article is part of a themed issue on Vascular Endothelium in Health and Disease. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-3
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Potassium channels and Neurovascular Coupling.
Circulation journal : official journal of the Japanese Circulation Society, 2010Co-Authors: Kathryn M. Dunn, Mark NelsonAbstract:Neuronal activity is communicated to the cerebral vasculature so that adequate perfusion of brain tissue is maintained at all levels of neuronal metabolism. An increase in neuronal activity is accompanied by vasodilation and an increase in local cerebral blood flow. This process, known as Neurovascular Coupling (NVC) or functional hyperemia, is essential for cerebral homeostasis and survival. Neuronal activity is encoded in astrocytic Ca(2+) signals that travel to astrocytic processes (;endfeet') encasing parenchymal arterioles within the brain. Astrocytic Ca(2+) signals cause the release of vasoactive substances to cause relaxation, and in some circumstances contraction, of the smooth muscle cells (SMCs) of parenchymal arterioles to modulate local cerebral blood flow. Activation of potassium channels in the SMCs has been proposed to mediate NVC. Here, the current state of knowledge of NVC and potassium channels in parenchymal arterioles is reviewed.
Paola Caruso - One of the best experts on this subject based on the ideXlab platform.
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small vessel disease related dementia an invalid Neurovascular Coupling
International Journal of Molecular Sciences, 2020Co-Authors: Rita Moretti, Paola CarusoAbstract:The arteriosclerosis-dependent alteration of brain perfusion is one of the major determinants in small vessel disease, since small vessels have a pivotal role in the brain’s autoregulation. Nevertheless, as far as we know, endothelium distress can potentiate the flow dysregulation and lead to subcortical vascular dementia that is related to small vessel disease (SVD), also being defined as subcortical vascular dementia (sVAD), as well as microglia activation, chronic hypoxia and hypoperfusion, vessel-tone dysregulation, altered astrocytes, and pericytes functioning blood-brain barrier disruption. The molecular basis of this pathology remains controversial. The apparent consequence (or a first event, too) is the macroscopic alteration of the Neurovascular Coupling. Here, we examined the possible mechanisms that lead a healthy aging process towards subcortical dementia. We remarked that SVD and white matter abnormalities related to age could be accelerated and potentiated by different vascular risk factors. Vascular function changes can be heavily influenced by genetic and epigenetic factors, which are, to the best of our knowledge, mostly unknown. Metabolic demands, active Neurovascular Coupling, correct glymphatic process, and adequate oxidative and inflammatory responses could be bulwarks in defense of the correct aging process; their impairments lead to a potentially catastrophic and non-reversible condition.