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A critical role for astrocytes in hypercapnic vasodilation in brain

journal contribution
posted on 2023-05-19, 10:59 authored by Howarth, C, Brad SutherlandBrad Sutherland, Choi, HB, Martin, C, Lind, BL, Khennouf, L, Ledue, JM, Pakan, JMP, Ko, RWY, Ellis-Davies, G, Lauritzen, M, Sibson, NR, Buchan, AM, MacVicar, BA
Cerebral bloodflow (CBF)is controlled by arterial blood pressure, arterial CO2 , arterial O2 , and brain activity andis largely constantinthe awake state. Although small changes in arterial CO2 are particularly potentto change CBF (1 mmHg variation in arterial CO2 changes CBF by 3%– 4%),the coupling mechanism is incompletely understood. Wetestedthe hypothesisthat 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-1that synthesizes PgE2 (microsomal prostaglandin E synthase-1) depends criticallyfor its vasodilator activity onthe level of glutathione inthe brain.We showthat, when glutathione levels are reduced, astrocyte calcium-evoked release of PgE2 is decreased and vasodilation triggered by increased 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 aging, stroke, or schizophrenia could lead to dysfunctional regulation of CBF and subsequent neuronal damage.


Publication title

Journal of Neuroscience










Tasmanian School of Medicine


Soc Neuroscience

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11 Dupont Circle, Nw, Ste 500, Washington, USA, Dc, 20036

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Expanding knowledge in the health sciences

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