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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.

References

  1. 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)

    ADS  CAS  Article  Google Scholar 

  2. 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)

    ADS  CAS  Article  Google Scholar 

  3. Goadsby, P. J. & Edvinsson, L. in Cerebral Blood Flow and Metabolism (ed. Krause, D. N.) 172–188 (Lippincott Williams & Wilkins, Philadelphia, 2002)

    Google Scholar 

  4. 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)

    CAS  Article  Google Scholar 

  5. 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)

    CAS  Article  Google Scholar 

  6. Simard, M., Arcuino, G., Takano, T., Liu, Q. S. & Nedergaard, M. Signaling at the gliovascular interface. J. Neurosci. 23, 9254–9262 (2003)

    CAS  Article  Google Scholar 

  7. 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)

    CAS  Article  Google Scholar 

  8. 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)

    CAS  Article  Google Scholar 

  9. Zhuo, L. et al. Live astrocytes visualized by green fluorescent protein in transgenic mice. Dev. Biol. 187, 36–42 (1997)

    CAS  Article  Google Scholar 

  10. 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)

    Google Scholar 

  11. Walz, W. & MacVicar, B. Electrophysiological properties of glial cells: comparison of brain slices with primary cultures. Brain Res. 443, 321–324 (1988)

    CAS  Article  Google Scholar 

  12. Duffy, S. & MacVicar, B. A. Adrenergic calcium signaling in astrocyte networks within the hippocampal slice. J. Neurosci. 15, 5535–5550 (1995)

    CAS  Article  Google Scholar 

  13. 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)

    CAS  Article  Google Scholar 

  14. Katsuki, H. & Okuda, S. Arachidonic acid as a neurotoxic and neurotrophic substance. Prog. Neurobiol. 46, 607–636 (1995)

    CAS  Article  Google Scholar 

  15. Street, I. P. et al. Slow- and tight-binding inhibitors of the 85-kDa human phospholipase A2. Biochemistry 32, 5935–5940 (1993)

    CAS  Article  Google Scholar 

  16. Roman, R. J. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol. Rev. 82, 131–185 (2002)

    CAS  Article  Google Scholar 

  17. Gebremedhin, D. et al. Production of 20-HETE and its role in autoregulation of cerebral blood flow. Circ. Res. 87, 60–65 (2000)

    CAS  Article  Google Scholar 

  18. Miyata, N. et al. HET0016, a potent and selective inhibitor of 20-HETE synthesizing enzyme. Br. J. Pharmacol. 133, 325–329 (2001)

    CAS  Article  Google Scholar 

  19. Zonta, M. et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nature Neurosci. 6, 43–50 (2003)

    CAS  Article  Google Scholar 

  20. Chillon, J. M. & Baumbach, G. L. in Cerebral Blood Flow and Metabolism (ed. Krause, D. N.) 395–412 (Lippincott Williams & Wilkins, Philadelphia, 2002)

    Google Scholar 

  21. 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)

    CAS  Article  Google Scholar 

  22. Dreier, J. P. et al. Ischaemia triggered by spreading neuronal activation is inhibited by vasodilators in rats. J. Physiol. (Lond.) 531, 515–526 (2001)

    CAS  Article  Google Scholar 

  23. Duffy, S. & MacVicar, B. A. In vitro ischemia promotes calcium influx and intracellular calcium release in hippocampal astrocytes. J. Neurosci. 16, 71–81 (1996)

    CAS  Article  Google Scholar 

  24. 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)

    ADS  CAS  Article  Google Scholar 

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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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