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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Chaigneau, E., Oheim, M., Audinat, E. & Charpak, S. Two-photon imaging of capillary blood flow in olfactory bulb glomeruli. Proc. Natl Acad. Sci. USA 100, 13081–13086 (2003)
Raichle, M. E., Hartman, B. K., Eichling, J. O. & Sharpe, L. G. Central noradrenergic regulation of cerebral blood flow and vascular permeability. Proc. Natl Acad. Sci. USA 72, 3726–3730 (1975)
Goadsby, P. J. & Edvinsson, L. in Cerebral Blood Flow and Metabolism (ed. Krause, D. N.) 172–188 (Lippincott Williams & Wilkins, Philadelphia, 2002)
Cohen, Z., Molinatti, G. & Hamel, E. Astroglial and vascular interactions of noradrenaline terminals in the rat cerebral cortex. J. Cereb. Blood Flow Metab. 17, 894–904 (1997)
Paspalas, C. D. & Papadopoulos, G. C. Ultrastructural relationships between noradrenergic nerve fibers and non-neuronal elements in the rat cerebral cortex. Glia 17, 133–146 (1996)
Simard, M., Arcuino, G., Takano, T., Liu, Q. S. & Nedergaard, M. Signaling at the gliovascular interface. J. Neurosci. 23, 9254–9262 (2003)
Soeller, C. & Cannell, M. B. Two-photon microscopy: imaging in scattering samples and three-dimensionally resolved flash photolysis. Microsc. Res. Tech. 47, 182–195 (1999)
Brown, E. B., Shear, J. B., Adams, S. R., Tsien, R. Y. & Webb, W. W. Photolysis of caged calcium in femtoliter volumes using two-photon excitation. Biophys. J. 76, 489–499 (1999)
Zhuo, L. et al. Live astrocytes visualized by green fluorescent protein in transgenic mice. Dev. Biol. 187, 36–42 (1997)
Kang, J. & Nedergaard, M. in Imaging Neurons: A Laboratory Manual (ed. Konnerth, A.) 42.1–42.11 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2000)
Walz, W. & MacVicar, B. Electrophysiological properties of glial cells: comparison of brain slices with primary cultures. Brain Res. 443, 321–324 (1988)
Duffy, S. & MacVicar, B. A. Adrenergic calcium signaling in astrocyte networks within the hippocampal slice. J. Neurosci. 15, 5535–5550 (1995)
Farooqui, A. A., Yang, H. C., Rosenberger, T. A. & Horrocks, L. A. Phospholipase A2 and its role in brain tissue. J. Neurochem. 69, 889–901 (1997)
Katsuki, H. & Okuda, S. Arachidonic acid as a neurotoxic and neurotrophic substance. Prog. Neurobiol. 46, 607–636 (1995)
Street, I. P. et al. Slow- and tight-binding inhibitors of the 85-kDa human phospholipase A2. Biochemistry 32, 5935–5940 (1993)
Roman, R. J. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol. Rev. 82, 131–185 (2002)
Gebremedhin, D. et al. Production of 20-HETE and its role in autoregulation of cerebral blood flow. Circ. Res. 87, 60–65 (2000)
Miyata, N. et al. HET0016, a potent and selective inhibitor of 20-HETE synthesizing enzyme. Br. J. Pharmacol. 133, 325–329 (2001)
Zonta, M. et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nature Neurosci. 6, 43–50 (2003)
Chillon, J. M. & Baumbach, G. L. in Cerebral Blood Flow and Metabolism (ed. Krause, D. N.) 395–412 (Lippincott Williams & Wilkins, Philadelphia, 2002)
Basarsky, T. A., Duffy, S. N., Andrew, R. D. & MacVicar, B. A. Imaging spreading depression and associated intracellular calcium waves in brain slices. J. Neurosci. 18, 7189–7199 (1998)
Dreier, J. P. et al. Ischaemia triggered by spreading neuronal activation is inhibited by vasodilators in rats. J. Physiol. (Lond.) 531, 515–526 (2001)
Duffy, S. & MacVicar, B. A. In vitro ischemia promotes calcium influx and intracellular calcium release in hippocampal astrocytes. J. Neurosci. 16, 71–81 (1996)
Xu, C., Zipfel, W., Shear, J. B., Williams, R. M. & Webb, W. W. Multiphoton fluorescence excitation: new spectral windows for biological nonlinear microscopy. Proc. Natl Acad. Sci. USA 93, 10763–10768 (1996)
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.
The authors declare that they have no competing financial interests.
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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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