A critical role for astrocytes in hypercapnic vasodilation in brain

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 - 2017/3/1

Y1 - 2017/3/1

N2 - Cerebral blood flow (CBF) is controlled by arterial blood pressure, arterialCO2, arterialO2, and brain activity and is largely constant in the awake state. Although small changes in arterial CO2 are particularly potent to change CBF (1mmHgvariation in arterial CO2 changes CBF by3%–4%), the coupling mechanism is incompletely understood. Wetested 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.Weshow that, when glutathione levels are reduced, astrocyte calcium-evoked release of PgE2 is decreased and vasodilation triggered by increased 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 aging, stroke, or schizophrenia could lead to dysfunctional regulation of CBF and subsequent neuronal damage.

AB - Cerebral blood flow (CBF) is controlled by arterial blood pressure, arterialCO2, arterialO2, and brain activity and is largely constant in the awake state. Although small changes in arterial CO2 are particularly potent to change CBF (1mmHgvariation in arterial CO2 changes CBF by3%–4%), the coupling mechanism is incompletely understood. Wetested 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.Weshow that, when glutathione levels are reduced, astrocyte calcium-evoked release of PgE2 is decreased and vasodilation triggered by increased 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 aging, stroke, or schizophrenia could lead to dysfunctional regulation of CBF and subsequent neuronal damage.

U2 - 10.1523/JNEUROSCI.0005-16.2016

DO - 10.1523/JNEUROSCI.0005-16.2016

M3 - Journal article

C2 - 28137973

SN - 0270-6474

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

IS - 9

ER -