A critical role for astrocytes in hypercapnic vasodilation in brain

Research output: Contribution to journalJournal articlepeer-review

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A critical role for astrocytes in hypercapnic vasodilation in brain. / Howarth, C; Sutherland, B A; Choi, H B; Martin, C; Lind, B L; Khennouf, L; LeDue, J M; Pakan, J M P; Ko, R W; Ellis-Davies, G C R; Lauritzen, M J; Sibson, N R; Buchan, A M; MacVicar, B A.

In: The Journal of Neuroscience, Vol. 37, No. 9, 2017, p. 2403-2414.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Howarth, C, Sutherland, BA, Choi, HB, Martin, C, Lind, BL, Khennouf, L, LeDue, JM, Pakan, JMP, Ko, RW, Ellis-Davies, GCR, Lauritzen, MJ, Sibson, NR, Buchan, AM & MacVicar, BA 2017, 'A critical role for astrocytes in hypercapnic vasodilation in brain', The Journal of Neuroscience, vol. 37, no. 9, pp. 2403-2414. https://doi.org/10.1523/JNEUROSCI.0005-16.2016

APA

Howarth, C., Sutherland, B. A., Choi, H. B., Martin, C., Lind, B. L., Khennouf, L., LeDue, J. M., Pakan, J. M. P., Ko, R. W., Ellis-Davies, G. C. R., Lauritzen, M. J., Sibson, N. R., Buchan, A. M., & MacVicar, B. A. (2017). A critical role for astrocytes in hypercapnic vasodilation in brain. The Journal of Neuroscience, 37(9), 2403-2414. https://doi.org/10.1523/JNEUROSCI.0005-16.2016

Vancouver

Howarth C, Sutherland BA, Choi HB, Martin C, Lind BL, Khennouf L et al. A critical role for astrocytes in hypercapnic vasodilation in brain. The Journal of Neuroscience. 2017;37(9):2403-2414. https://doi.org/10.1523/JNEUROSCI.0005-16.2016

Author

Howarth, C ; Sutherland, B A ; Choi, H B ; Martin, C ; Lind, B L ; Khennouf, L ; LeDue, J M ; Pakan, J M P ; Ko, R W ; Ellis-Davies, G C R ; Lauritzen, M J ; Sibson, N R ; Buchan, A M ; MacVicar, B A. / A critical role for astrocytes in hypercapnic vasodilation in brain. In: The Journal of Neuroscience. 2017 ; Vol. 37, No. 9. pp. 2403-2414.

Bibtex

@article{21f71e76fea841ab8cec337c3c8d2969,
title = "A critical role for astrocytes in hypercapnic vasodilation in brain",
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 [Ca(2+)]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 [Ca(2+)]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.SIGNIFICANCE STATEMENT: Neuronal activity leads to the generation of CO2, which has previously been shown to evoke cerebral blood flow (CBF) increases via the release of the vasodilator PgE2 We demonstrate that hypercapnia (increased CO2) evokes increases in astrocyte calcium signaling which in turn stimulates COX-1 activity and generates downstream PgE2 production. We demonstrate that astrocyte calcium-evoked production of the vasodilator, PgE2, is critically dependent on brain levels of the antioxidant, glutathione. These data suggest a novel role for astrocytes in the regulation of CO2-evoked CBF responses. Furthermore, these results suggest that depleted glutathione levels, which occur in ageing and stroke, will give rise to dysfunctional cerebral blood flow regulation and may result in subsequent neuronal damage.",
author = "C Howarth and Sutherland, {B A} and Choi, {H B} and C Martin and Lind, {B L} and L Khennouf and LeDue, {J M} and Pakan, {J M P} and Ko, {R W} and Ellis-Davies, {G C R} and Lauritzen, {M J} and Sibson, {N R} and Buchan, {A M} and MacVicar, {B A}",
note = "Copyright {\textcopyright} 2017 Howarth et al.",
year = "2017",
doi = "10.1523/JNEUROSCI.0005-16.2016",
language = "English",
volume = "37",
pages = "2403--2414",
journal = "The Journal of neuroscience : the official journal of the Society for Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "9",

}

RIS

TY - JOUR

T1 - A critical role for astrocytes in hypercapnic vasodilation in brain

AU - Howarth, C

AU - Sutherland, B A

AU - Choi, H B

AU - Martin, C

AU - Lind, B L

AU - Khennouf, L

AU - LeDue, J M

AU - Pakan, J M P

AU - Ko, R W

AU - Ellis-Davies, G C R

AU - Lauritzen, M J

AU - Sibson, N R

AU - Buchan, A M

AU - MacVicar, B A

N1 - Copyright © 2017 Howarth et al.

PY - 2017

Y1 - 2017

N2 - 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 [Ca(2+)]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 [Ca(2+)]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.SIGNIFICANCE STATEMENT: Neuronal activity leads to the generation of CO2, which has previously been shown to evoke cerebral blood flow (CBF) increases via the release of the vasodilator PgE2 We demonstrate that hypercapnia (increased CO2) evokes increases in astrocyte calcium signaling which in turn stimulates COX-1 activity and generates downstream PgE2 production. We demonstrate that astrocyte calcium-evoked production of the vasodilator, PgE2, is critically dependent on brain levels of the antioxidant, glutathione. These data suggest a novel role for astrocytes in the regulation of CO2-evoked CBF responses. Furthermore, these results suggest that depleted glutathione levels, which occur in ageing and stroke, will give rise to dysfunctional cerebral blood flow regulation and may result in subsequent neuronal damage.

AB - 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 [Ca(2+)]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 [Ca(2+)]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.SIGNIFICANCE STATEMENT: Neuronal activity leads to the generation of CO2, which has previously been shown to evoke cerebral blood flow (CBF) increases via the release of the vasodilator PgE2 We demonstrate that hypercapnia (increased CO2) evokes increases in astrocyte calcium signaling which in turn stimulates COX-1 activity and generates downstream PgE2 production. We demonstrate that astrocyte calcium-evoked production of the vasodilator, PgE2, is critically dependent on brain levels of the antioxidant, glutathione. These data suggest a novel role for astrocytes in the regulation of CO2-evoked CBF responses. Furthermore, these results suggest that depleted glutathione levels, which occur in ageing and stroke, will give rise to dysfunctional cerebral blood flow regulation and may result in subsequent neuronal damage.

U2 - 10.1523/JNEUROSCI.0005-16.2016

DO - 10.1523/JNEUROSCI.0005-16.2016

M3 - Journal article

C2 - 28137973

VL - 37

SP - 2403

EP - 2414

JO - The Journal of neuroscience : the official journal of the Society for Neuroscience

JF - The Journal of neuroscience : the official journal of the Society for Neuroscience

SN - 0270-6474

IS - 9

ER -

ID: 172962501