Calcium transients in astrocyte endfeet cause cerebrovascular constrictions

Abstract

Cerebral blood flow (CBF) is coupled to neuronal activity and is imaged in vivo to map brain activation1. CBF is also modified by afferent projection fibres that release vasoactive neurotransmitters2,3 in the perivascular region, principally on the astrocyte endfeet4,5 that outline cerebral blood vessels6. However, the role of astrocytes in the regulation of cerebrovascular tone remains uncertain. Here we determine the impact of intracellular Ca2+ concentrations ([Ca2+]i) in astrocytes on the diameter of small arterioles by using two-photon Ca2+ uncaging7,8 to increase [Ca2+]i. Vascular constrictions occurred when Ca2+ waves evoked by uncaging propagated into the astrocyte endfeet and caused large increases in [Ca2+]i. The vasoactive neurotransmitter noradrenaline2,3 increased [Ca2+]i in the astrocyte endfeet, the peak of which preceded the onset of arteriole constriction. Depressing increases in astrocyte [Ca2+]i with BAPTA inhibited the vascular constrictions in noradrenaline. We find that constrictions induced in the cerebrovasculature by increased [Ca2+]i in astrocyte endfeet are generated through the phospholipase A2–arachidonic acid pathway and 20-hydroxyeicosatetraenoic acid production. Vasoconstriction by astrocytes is a previously unknown mechanism for the regulation of CBF.

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Figure 1: Two-photon photolysis of caged Ca2+ in identified astrocytes initiates Ca2+ waves that propagate to astrocyte endfeet and induce arteriole constriction.
Figure 2: The extent of vascular constrictions was related to the number of endfeet showing increased [Ca2+]i.
Figure 3: Noradrenaline-induced Ca2+ elevations in astrocyte endfeet precede the onset of vessel constriction.
Figure 4: Increased [Ca2+]i in astrocyte endfeet causes cerebrovascular constrictions.

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Acknowledgements

We thank A. G. Phillips, Y. T. Wang and T. Murphy for comments on the manuscript, and D. Feighan for technical assistance. S.J.M. was supported by a Canadian Heart and Stroke Fellowship. B.A.M. is a Canada Research Chair in Neuroscience and Michael Smith Distinguished Scholar. Work was supported by Canadian Institutes of Health Research and the Canadian Stroke Network.

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Correspondence to Brian A. MacVicar.

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Mulligan, S., MacVicar, B. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431, 195–199 (2004). https://doi.org/10.1038/nature02827

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