Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 234, Issue 4, Pages 3538-3554Publisher
WILEY
DOI: 10.1002/jcp.26953
Keywords
Ca2+ oscillations; endothelial cells; glutamate; neurovascular coupling (NVC); nitric oxide
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Funding
- Universita degli Studi di Pavia
- Italian Ministry of Education, University and Research (MIUR) [2018-2022]
- European Union grant Human Brain Project [HBP-604102]
- Centro Studi e Ricerche Enrico Fermi [13(14)]
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The neurotransmitter glutamate increases cerebral blood flowby activating postsynaptic neurons and presynaptic glial cells within the neurovascular unit. Glutamate does so by causing an increase in intracellular Ca2+ concentration ([Ca2+](i)) in the target cells, which activates the Ca2+/Calmodulin-dependent nitric oxide (NO) synthaseto release NO. It is unclear whether brain endothelial cells also sense glutamate through an elevation in [Ca2+](i) and NO production. The current study assessed whether and how glutamate drives Ca2+-dependent NO release in bEND5 cells, an established model of brain endothelial cells. We found that glutamate induced a dose-dependent oscillatory increase in [Ca2+](i), which was maximally activated at 200M and inhibited by -methyl-4-carboxyphenylglycine, a selective blocker of Group 1 metabotropic glutamate receptors. Glutamate-induced intracellular Ca2+ oscillations were triggered by rhythmic endogenous Ca2+ mobilization and maintained over time by extracellular Ca2+ entry. Pharmacological manipulation revealed that glutamate-induced endogenous Ca2+ release was mediated by InsP(3)-sensitive receptors and nicotinic acid adenine dinucleotide phosphate (NAADP) gated two-pore channel 1. Constitutive store-operated Ca2+ entry mediated Ca2+ entry during ongoing Ca2+ oscillations. Finally, glutamate evoked a robust, although delayed increase in NO levels, which was blocked by pharmacologically inhibition of the accompanying intracellular Ca2+ signals. Of note, glutamate induced Ca2+-dependent NO release also in hCMEC/D3 cells, an established model of human brain microvascular endothelial cells. This investigation demonstrates for the first time that metabotropic glutamate-induced intracellular Ca2+ oscillations and NO release have the potential to impact on neurovascular coupling in the brain.
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