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Brain metabolism dictates the polarity of astrocyte control over arterioles

Nature volume 456, pages 745–749 (2008)Cite this article

Abstract

Calcium signalling in astrocytes couples changes in neural activity to alterations in cerebral blood flow by eliciting vasoconstriction or vasodilation of arterioles. However, the mechanism for how these opposite astrocyte influences provide appropriate changes in vessel tone within an environment that has dynamic metabolic requirements remains unclear. Here we show that the ability of astrocytes to induce vasodilations over vasoconstrictions relies on the metabolic state of the rat brain tissue. When oxygen availability is lowered and astrocyte calcium concentration is elevated, astrocyte glycolysis and lactate release are maximized. External lactate attenuates transporter-mediated uptake from the extracellular space of prostaglandin E2, leading to accumulation and subsequent vasodilation. In conditions of low oxygen concentration extracellular adenosine also increases, which blocks astrocyte-mediated constriction, facilitating dilation. These data reveal the role of metabolic substrates in regulating brain blood flow and provide a mechanism for differential astrocyte control over cerebrovascular diameter during different states of brain activation.

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Figure 1: Lowering p O2 converts vasoconstriction to vasodilation.
Figure 2: O2-mediated conversion to astrocyte-mediated vasodilation requires COX and PGE2.
Figure 3: Low O 2 facilitates lactate and PGE 2 release and enhances astrocyte glycolysis.
Figure 4: Glycolysis and lactate release is required for vasodilations.
Figure 5: Raising adenosine and PGE 2 levels converts the vessel response.

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Acknowledgements

We thank T. Murphy, T. Phillips and Y. Tian Wang for reading an earlier version of the manuscript. T34 was a gift from V. L. Schuster and Y. Chi. This work was supported by an operating grant from the Canadian Institutes of Health Research. B.A.M. is a Canada Research Chair and a Michael Smith Foundation for Health Research (MSFHR) Distinguished Scholar. G.R.J.G. is supported by fellowships from the Alberta Heritage Foundation for Medical Research, MSFHR and the Natural Science and Engineering Council of Canada. H.B.C. is supported by postdoctoral fellowships from Wilms Foundation and the Heart and Stroke Foundation of Canada.

Author Contributions G.R.J.G. and B.A.M. designed the imaging experiments and wrote the manuscript. G.R.J.G. performed the imaging experiments and analysis, took slice pO2 measurements and tested the effects of synaptic activation on vasomotion. H.B.C., G.R.J.G. and B.A.M. designed the lactate and PGE2 experiments. H.B.C. and B.A.M. designed the immunohistochemistry experiments. H.B.C. performed the lactate and PGE2 measurements and analysis and the immunohistochemistry. R.L.R. performed the extracellular field recordings examining adenosine tone. G.C.R.E.-D. designed and synthesized the calcium cage. All authors helped to edit the manuscript.

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  1. Department of Psychiatry, Brain Research Centre, University of British Columbia, British Columbia T2N 2B5, Canada

    Grant R. J. Gordon, Hyun B. Choi, Ravi L. Rungta & Brian A. MacVicar

  2. Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA,

    Graham C. R. Ellis-Davies

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Correspondence to Brian A. MacVicar.

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Gordon, G., Choi, H., Rungta, R. et al. Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456, 745–749 (2008). https://doi.org/10.1038/nature07525

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