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 [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 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.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 aging and stroke, will give rise to dysfunctional CBF regulation and may result in subsequent neuronal damage.

Brain metabolic sensing and metabolic signaling at the level of an astrocyte

“…Finally, a recent study has suggested that astrocytes may also mediate cerebrovascular responses to CO 2 . Howarth and colleagues (2017) reported that in anesthetized mice, increases in the level of inspired CO 2 trigger [Ca 2+ ] i responses in cortical astrocytes, which in turn may evoke cerebral vessel dilations via stimulation of COX‐1 activity followed by PgE 2 release and its action on cerebrovascular smooth muscle cells (Howarth et al, ).…”

Electrochemical carbon fiber-based technique for simultaneous recordings of brain tissue PO2, pH, and extracellular field potentials

“…The ‘feed-forward’ hypothesis of neurovascular coupling (Attwell et al 2010) suggests that neurotransmitters released during neuronal activity signal to astrocytes and pericytes to induce dilation of the cerebral vasculature (Mishra et al 2016). However, astrocytes are also sensitive to changes in partial pressure of oxygen (PO 2 ) (Angelova et al 2015) as well as CO 2 and protons (H + ) (Gourine et al 2010; Howarth et al 2017; Karagiannis et al 2016). Changes in brain tissue PO 2 , PCO 2 and pH correlate with changes in neuronal activity and could contribute to neurovascular coupling via a metabolic feed-back mechanism, as was originally proposed by Roy and Sherrington (Roy and Sherrington 1890).…”

D-serine released by astrocytes in brainstem regulates breathing response to CO2 levels

“…ATP is released from the ventral medullary surface in response to CO 2 and [H + ] 3 and contributes to the activation of the respiratory network 3 , 4 . Astrocytes can sense CO 2 and H + in neocortex 5 , 6 and act as chemosensory interoceptors in the rat rostral medullary brainstem 4 , 7 where they release ATP 4 , 7 to activate H + -sensitive retrotrapezoid neurons 4 , 8 – 10 in response to acidosis or hypercapnia (increased levels of CO 2 ) 4 . However, experimental results supporting the theory that hypercapnia in the caudal medullary brainstem is also mediated by ATP have been elusive 11 .…”