Howarth, C., Sutherland, B., Choi, H.B. et al. (11 more authors) (2017) A critical role for astrocytes in hypercapnic vasodilation in brain. Journal of Neuroscience. ISSN 0270-6474
Abstract
Cerebral blood flow (CBF) is controlled by arterial blood pressure, arterial CO2, arterial O2, and brain activity and is largely constant in the awake state. Although small changes in arterial CO2 are particularly potent to change CBF (1 mmHg variation in arterial CO2 changes CBF by 3-4%), the coupling mechanism is incompletely understood. We tested the hypothesis that astrocytic prostaglandin E2 (PgE2) plays a key role for cerebrovascular CO2 reactivity and that preserved synthesis of glutathione is essential for the full development of this response.
We combined two-photon imaging microscopy in brain slices with in vivo work in rats and C57Bl/6J mice to examine the hemodynamic responses to CO2 and somatosensory stimulation before and after inhibition of astrocytic glutathione and PgE2 synthesis. We demonstrate that hypercapnia (increased CO2) evokes an increase in astrocyte [Ca2+]i and stimulates COX-1 activity. The enzyme downstream of COX-1 that synthesizes PgE2 (microsomal prostaglandin E synthase-1) depends critically for its vasodilator activity on the level of glutathione in the brain. We show that when glutathione levels are reduced, astrocyte calcium-evoked release of PgE2 is decreased and vasodilation triggered by astrocyte [Ca2+]i in vitro and by hypercapnia in vivo is inhibited.
Astrocyte synthetic pathways, dependent on glutathione, are involved in cerebrovascular reactivity to CO2. Reductions in glutathione levels in ageing, stroke or schizophrenia could lead to dysfunctional regulation of CBF and subsequent neuronal damage.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 This is an open-access article distributed under the terms of the Creative Commons Attribution License Creative Commons Attribution 4.0 International, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > Department of Psychology (Sheffield) |
Funding Information: | Funder Grant number ROYAL SOCIETY UF080113 ROYAL SOCIETY UF130327 WELLCOME TRUST (THE) 093223/B/10/Z |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 23 Feb 2017 16:17 |
Last Modified: | 23 Feb 2017 16:25 |
Published Version: | https://doi.org/10.1523/JNEUROSCI.0005-16.2016 |
Status: | Published |
Publisher: | Society for Neuroscience |
Refereed: | Yes |
Identification Number: | 10.1523/JNEUROSCI.0005-16.2016 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:109756 |