Neurovascular-neuroenergetic coupling axis in the brain: master regulation by nitric oxide and consequences in aging and neurodegeneration

Lourenço, Cátia F.; Ledo, Ana; Barbosa, Rui M.; Laranjinha, João

doi:10.1016/j.freeradbiomed.2017.04.026

Cited by 76 publications

(66 citation statements)

References 234 publications

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“…An increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) within the dendritic tree is the crucial signal that triggers the synthesis and release of vasoactive messengers in response to excitatory synaptic inputs [ 2 , 4 , 9 , 34 ]. For instance, glutamate stimulates post-synaptic N -methyl- d -aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazol epropionic acid (AMPA) receptors to induce extracellular Ca 2+ entry and recruit the Ca 2+ /calmodulin (Ca 2+ /CaM)-dependent neuronal nitric oxide (NO) synthase (nNOS) in hippocampal and cerebellar GABA interneurons [ 10 , 25 , 28 , 33 , 35 ]. The following NO release elicits arteriole vasodilation by inducing VSMC hyperpolarization and relaxation through a soluble guanylate cyclase/protein kinase G (PKG)-dependent mechanism (see below) [ 13 , 26 , 35 , 36 , 37 ].…”

Section: Neurovascular Couplingmentioning

confidence: 99%

“…For instance, glutamate stimulates post-synaptic N -methyl- d -aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazol epropionic acid (AMPA) receptors to induce extracellular Ca 2+ entry and recruit the Ca 2+ /calmodulin (Ca 2+ /CaM)-dependent neuronal nitric oxide (NO) synthase (nNOS) in hippocampal and cerebellar GABA interneurons [ 10 , 25 , 28 , 33 , 35 ]. The following NO release elicits arteriole vasodilation by inducing VSMC hyperpolarization and relaxation through a soluble guanylate cyclase/protein kinase G (PKG)-dependent mechanism (see below) [ 13 , 26 , 35 , 36 , 37 ]. Conversely, NMDA receptor (NMDAR)-mediated Ca 2+ entry in synaptically-activated pyramidal neurons of the somatosensory cortex engages cyclooxygenase 2, which catalyzes the synthesis of the powerful vasodilator, prostaglandin E2 (PGE2), which acts through EP2 and EP4 receptors on VSMCs [ 27 , 28 ].…”

Section: Neurovascular Couplingmentioning

confidence: 99%

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The Role of Endothelial Ca2+ Signaling in Neurovascular Coupling: A View from the Lumen

Guerra

Lucariello

Perna

et al. 2018

IJMS

104

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Background: Neurovascular coupling (NVC) is the mechanism whereby an increase in neuronal activity (NA) leads to local elevation in cerebral blood flow (CBF) to match the metabolic requirements of firing neurons. Following synaptic activity, an increase in neuronal and/or astrocyte Ca2+ concentration leads to the synthesis of multiple vasoactive messengers. Curiously, the role of endothelial Ca2+ signaling in NVC has been rather neglected, although endothelial cells are known to control the vascular tone in a Ca2+-dependent manner throughout peripheral vasculature. Methods: We analyzed the literature in search of the most recent updates on the potential role of endothelial Ca2+ signaling in NVC. Results: We found that several neurotransmitters (i.e., glutamate and acetylcholine) and neuromodulators (e.g., ATP) can induce dilation of cerebral vessels by inducing an increase in endothelial Ca2+ concentration. This, in turn, results in nitric oxide or prostaglandin E2 release or activate intermediate and small-conductance Ca2+-activated K+ channels, which are responsible for endothelial-dependent hyperpolarization (EDH). In addition, brain endothelial cells express multiple transient receptor potential (TRP) channels (i.e., TRPC3, TRPV3, TRPV4, TRPA1), which induce vasodilation by activating EDH. Conclusions: It is possible to conclude that endothelial Ca2+ signaling is an emerging pathway in the control of NVC.

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Section: Neurovascular Couplingmentioning

confidence: 99%

Section: Neurovascular Couplingmentioning

confidence: 99%

The Role of Endothelial Ca2+ Signaling in Neurovascular Coupling: A View from the Lumen

Guerra

Lucariello

Perna

et al. 2018

IJMS

104

View full text Add to dashboard Cite

show abstract

“…Since many inflammatory responses are beneficial, directing and instructing the inflammatory machinery may be a better therapeutic objective than suppressing it". Loss of olfaction might be the time, and the olfactory bulb could be the place, to realize that impending neurodegeneration is at its acute stage, a stage that might respond to immune manipulation, neuropeptide therapy and nitric oxide regulation [47][48][49].…”

Section: Discussionmentioning

confidence: 99%

Changes in Vascular and Immune Cell Content of an LPS Treated Rat Olfactory Bulb PD Model, Measured by Fluorescence Deconvolution Microscopy

Bick¹,

Poindexter²,

Doursout³

2017

J Cytokine Biol

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Objective: We have previously shown changes in protein, immune cell, nitric oxide a neurotrophic factor content and distribution in the olfactory bulb of an endotoxin-treated rat model, as all these factors have been shown to be involved in neurodegeneration. We expanded our studies by fluorescently imaging smooth muscle actin and endothelial nitric oxide synthase (eNOS), both markers of blood vessels, to investigate loss of vasculature content, as well as imaging locations and quantities of immune cells. The work was performed to shed further light on associations between vessel integrity and immune cell initiated endothelial disruption. Our goal was to demonstrate that cytokine production, NOS induction and immune cell increases, are likely part of the process that leads to a loss of olfaction and dopaminergic signaling and includes vascular perturbations.Methods: Rats were sacrificed following lipopolysaccharide (LPS) treatment. Olfactory bulbs were harvested, sectioned from top to bottom to include the tract and sensory neurons, and probed for markers of inflammation. Inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), eNOS, interleukin-1 beta (IL-1β), TNF-α, interleukin-6, glial cell derived neurotrophic factor (GDNF) and circulating nitric oxide (NO) were imaged together with tagged macrophages, T-cells, B-cells and neutrophils.Results: Serum NO levels indicated that an inflammatory episode had occurred, being significantly higher in treated animals, with tissue levels of NOS elevated for an extended period of time. Immune cell clusters were seen in a number of areas and the localization of NOS isomers suggests that they have divergent roles in neurodegeneration. For instance, eNOS was associated with blood vessels, iNOS with glial and matrix cells and nNOS with glial cells and neurons. T and B-cell numbers showed a sustained increase; neutrophil numbers rapidly increased then returned to baseline levels; macrophage numbers increased and remained high; LAMP positive cell numbers (NK-cells) increased and remained high; GDNF content increased; IL-6, TNF-α and IL-1β levels all rapidly increased, before dropping to untreated levels, while circulating, NO levels increased dramatically. Of interest, the images of vascular content, immune cell content, eNOS and smooth muscle actin, allowed us to show detrimental interactions between cells, factors and vessels. Our data show that the majority of the vessels were intact, though sections of interest were 'extracted' to reveal possible leaky areas. Specific sites of IL-6 positive lymphocyte clustering were noted around vessels, suggesting that interactions are occurring that lead to disruptions of blood vessel tunicae, allowing the internalization of circulating cells and subsequent cytokine-initiated endothelial cell death. Conclusion:Our findings suggest that protective GDNF and eNOS, which maintains vascular tone, are possibly synthesized too late to combat cytokine initiated neuron damage, glial activation and chronic loss of va...

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“…During the lifespan, a number of different structural, functional and molecular changes can happen from innumerable multifactorial changes resulting in the normal neuronal ageing and often in neurodegeneration appearing constantly in the nervous system [1,2]. It is believed that the ageing process programmed cell death) rather than inflammation, ischemia, or another mechanism [2].…”

Section: Brain Agingmentioning

confidence: 99%

“…It is believed that the ageing process programmed cell death) rather than inflammation, ischemia, or another mechanism [2]. In some areas, however, dendritic connections may increase, perhaps as a result of compensatory plasticity.…”

Section: Brain Agingmentioning

confidence: 99%

The Role of Neuroimaging in the Ageing Brain

Ambrosi¹,

Junior²,

Ambrosi³

2017

JNSK

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It is of crucial importance to recognize the changes that occur in the brain ageing. Although neuroimaging studies are important tools used in the evaluation of changes in brain ageing mainly through the exclusion of comorbidities and neurodegenerative disorders, their role is still controversial. In this minireview, we discuss the main aspects of brain ageing, the differences between the young and old brain, the neuroimaging techniques and the use of neuroimaging to assess brain age. Differentiating the differences between normal structural and pathological ageing will provide a deeper understanding of the ageing process of the brain and will bring us new perspectives on biomarkers.

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Neurovascular-neuroenergetic coupling axis in the brain: master regulation by nitric oxide and consequences in aging and neurodegeneration

Cited by 76 publications

References 234 publications

The Role of Endothelial Ca2+ Signaling in Neurovascular Coupling: A View from the Lumen

The Role of Endothelial Ca2+ Signaling in Neurovascular Coupling: A View from the Lumen

Changes in Vascular and Immune Cell Content of an LPS Treated Rat Olfactory Bulb PD Model, Measured by Fluorescence Deconvolution Microscopy

The Role of Neuroimaging in the Ageing Brain

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