Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches.
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Attwell, D. & Laughlin, S. B. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab. 21, 1133–1145 (2001).
Leffler, C. W., Busija, D. W., Mirro, R., Armstead, W. M. & Beasley, D. G. Effects of ischemia on brain blood flow and oxygen consumption of newborn pigs. Am. J. Physiol. 257, H1917–H1926 (1989).
Girouard, H. & Iadecola, C. Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J. Appl. Physiol. 100, 328–335 (2006).
Baptiste, D. C. & Fehlings, M. Pharmacological approaches to repair the injured spinal cord. J. Neurotrauma 23, 318–334 (2006).
Tian, R. et al. Role of extracellular and intracellular acidosis for hypercapnia-induced inhibition of tension of isolated rat cerebral arteries. Circ. Res. 76, 269–275 (1995).
Mintun, M. A. et al. Blood flow and oxygen delivery to human brain during functional activity: theoretical modeling and experimental data. Proc. Natl Acad. Sci USA 98, 6859–6864 (2001).
Lindauer, U. et al. Neurovascular coupling in rat brain operates independent of hemoglobin deoxygenation. J. Cereb. Blood Flow Metab. 30, 757–768 (2010). Challenges brain slice data showing that high [O 2 ] converts dilations seen at physiological [O 2 ] into constrictions.
Powers, W. J., Hirsch, I. B. & Cryer, P. E. Effect of stepped hypoglycemia on regional cerebral blood flow response to physiological brain activation. Am. J. Physiol. 270, H554–H559 (1996).
Astrup, J. et al. Evidence against H+ and K+ as main factors for the control of cerebral blood flow: a microelectrode study. Ciba Found. Symp. 56, 313–337 (1978).
Makani, S. & Chesler, M. Rapid rise of extracellular pH evoked by neural activity is generated by the plasma membrane calcium ATPase. J. Neurophysiol. 103, 667–676 (2010).
Ko, K. R., Ngai, A. C. & Winn, H. R. Role of adenosine in regulation of regional cerebral blood flow in sensory cortex. Am. J. Physiol. Heart Circ. Physiol. 259, H1703–H1708 (1990).
Ido, Y., Chang, K., Woolsey, T. A. & Williamson, J. R. NADH: sensor of blood flow need in brain, muscle and other tissues. FASEB J. 15, 1419–1421 (2001).
Akgören, N., Fabricius, M. & Lauritzen, M. Importance of nitric oxide for local increases of blood flow in rat cerebellar cortex during electrical stimulation. Proc. Natl Acad. Sci. USA 91, 5903–5907 (1994).
Li, J. & Iadecola, C. Nitric oxide and adenosine mediate vasodilation during functional activation in cerebellar cortex. Neuropharmacology 33, 1453–1461 (1994).
Zonta, M. et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nature Neurosci. 6, 43–50 (2003).
Nielsen, A. N. & Lauritzen, M. Coupling and uncoupling of activity-dependent increases of neuronal activity and blood flow in rat somatosensory cortex. J. Physiol. 533, 773–785 (2001).
Chaigneau, E. et al. The relationship between blood flow and neuronal activity in the rodent olfactory bulb. J. Neurosci. 27, 6452–6460 (2007).
Offenhauser, N., Thomsen, K., Caesar, K. & Lauritzen, M. Activity induced tissue oxygenation changes in rat cerebellar cortex: interplay of postsynaptic activation and blood flow. J. Physiol. 565, 279–294 (2005).
Lecoq, J. et al. Odor-evoked oxygen consumption by action potential and synaptic transmission in the olfactory bulb. J. Neurosci. 29, 1424–1433 (2009).
St Lawrence, K. S., Ye, F. Q., Lewis, B. K., Frank, J. A. & McLaughlin, A. C. Measuring the effects of indomethacin on changes in cerebral oxidative metabolism and cerebral blood flow during sensorimotor activation. Magn. Reson. Med. 50, 99–106 (2003).
Busija, D. W., Bari, F., Domoki, F. & Louis, T. Mechanisms involved in the cerebrovascular dilator effects of N-methyl-D-aspartate in cerebral cortex. Brain Res. Rev. 56, 89–100 (2007).
Ma, J., Ayata, C., Huang, P. L., Fishman, M. C. & Moskowitz, M. A. Regional cerebral blood flow response to vibrissal stimulation in mice lacking type I NOS gene expression. Am. J. Physiol. 270, H1085–H1090 (1996).
Lindauer, U., Megow, D., Matsuda, H. & Dirnagl, U. Nitric oxide: a modulator, but not a mediator, of neurovascular coupling in rat somatosensory cortex. Am. J. Physiol. Heart Circ. Physiol. 277, H799–H811 (1999).
Akgören, N., Dalgaard, P. & Lauritzen, M. Cerebral blood flow increases evoked by electrical stimulation of rat cerebellar cortex: relation to excitatory synaptic activity and nitric oxide synthesis. Brain Res. 710, 204–214 (1996).
Yang, G., Zhang, Y., Ross, M. E. & Iadecola, C. Attenuation of activity-induced increases in cerebellar blood flow in mice lacking neuronal nitric oxide synthase. Am. J. Physiol. Heart Circ. Physiol. 285, H298–H304 (2003).
Cauli, B. et al. Cortical GABA interneurons in neurovascular coupling: relays for subcortical vasoactive pathways. J. Neurosci. 24, 8940–8949 (2004).
Kocharyan, A., Fernandes, P., Tong, X. K., Vaucher, E. & Hamel, E. Specific subtypes of cortical GABA interneurons contribute to the neurovascular coupling response to basal forebrain stimulation. J. Cereb. Blood Flow Metab. 28, 221–231 (2008).
Knot, H. J., Zimmermann, P. A. & Nelson, M. T. Extracellular K+-induced hyperpolarizations and dilations of rat coronary and cerebral arteries involve inward rectifier K+ channels. J. Physiol. 492, 419–430 (1996).
Paulson, O. B. & Newman, E. A. Does the release of potassium from astrocyte endfeet regulate cerebral blood flow? Science 237, 896–898 (1987).
Metea, M. R., Kofuji, P. & Newman, E. A. Neurovascular coupling is not mediated by potassium siphoning from glial cells. J. Neurosci. 27, 2468–2471 (2007).
Porter, J. T. & McCarthy, K. D. Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals. J. Neurosci. 16, 5073–5081 (1996).
Filosa, J. A. et al. Local potassium signaling couples neuronal activity to vasodilation in the brain. Nature Neurosci. 9, 1397–1403 (2006).
Ou, J. W. et al. Ca2+- and thromboxane-dependent distribution of MaxiK channels in cultured astrocytes: from microtubules to the plasma membrane. Glia 57, 1280–1295 (2009).
Metea, M. R. & Newman, E. A. Glial cells dilate and constrict blood vessels: a mechanism of neurovascular coupling. J. Neurosci. 26, 2862–2870 (2006).
Gordon, G. R. J. et al. Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456, 745–749 (2008). Shows that O 2 level profoundly affects vascular response to neuronal activity.
Peng, X. et al. Suppression of functional hyperemia to vibrissal stimulation in the rat by epoxygenase inhibitors. Am. J. Physiol. Heart Circ. Physiol. 283, H2029–H2037 (2002).
Peng, X., Zhang, C., Alkayed, N. J., Harder, D. R. & Koehler, R. C. Dependency of cortical functional hyperemia to forepaw stimulation on epoxygenase and nitric oxide synthase activities in rats. J. Cereb. Blood Flow Metab. 24, 509–517 (2004).
Davis, R. J. et al. EP4 prostanoid receptor-mediated vasodilation of human middle cerebral arteries. Br. J. Pharmacol. 141, 580–585 (2004).
Takata, F. et al. Adrenomedullin-induced relaxation of rat brain pericytes is related to the reduced phosphorylation of myosin light chain through the cAMP/PKA signaling pathway. Neurosci. Lett. 449, 71–75 (2009).
Serebryakov, V., Zakharenko, S., Snetkov, V. & Takeda, K. Effects of prostaglandins E1 and E2 on cultured smooth muscle cells and strips of rat aorta. Prostaglandins 47, 353–365 (1994).
Campbell, W. B., Gebremedhin, D., Pratt, P. F. & Harder, D. R. Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ. Res. 78, 415–423 (1996).
Behm, D. J., Ogbonna, A., Wu, C., Burns-Kurtis, C. L. & Douglas, S. A. Epoxyeicosatrienoic acids function as selective, endogenous antagonists of native thromboxane receptors: identification of a novel mechanism of vasodilation. J. Pharmacol. Exp. Ther. 328, 231–239 (2009).
Takano, T. et al. Astrocyte mediated control of cerebral blood flow. Nature Neurosci. 9, 260–267 (2006). Extends, to the in vivo situation, the Zonta et al . (2003) result that astrocytes control cerebral blood flow.
Mulligan, S. J. & MacVicar, B. A. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431, 195–199 (2004).
Blanco, V. M., Stern, J. E. & Filosa, J. Tone-dependent vascular responses to astrocyte-derived signals. Am. J. Physiol. Heart Circ. Physiol. 294, H2855–H2863 (2008).
Chuquet, J., Hollender, L. & Nimchinsky, E. A. High-resolution in vivo imaging of the neurovascular unit during spreading depression. J. Neurosci. 27, 4036–4044 (2007).
Kis, B., Snipes, J. A., Isse, T., Nagy, K. & Busija, D. W. Putative cyclooxygenase-3 expression in rat brain cells. J. Cereb. Blood Flow Metab. 23, 1287–1292 (2003).
Hirst, W. D. et al. Expression of COX-2 by normal and reactive astrocytes in the adult rat central nervous system. Mol. Cell. Neurosci. 13, 57–68 (1999).
Niwa, K., Araki, E., Morham, S. G., Ross, M. E. & Iadecola, C. Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex. J. Neurosci. 20, 763–770 (2000).
Petzold, G. C., Albeanu, D. F., Sato, T. F. & Murthy, V. N. Coupling of neural activity to blood flow in olfactory glomeruli is mediated by astrocytic pathways. Neuron 58, 897–910 (2008).
Schummers, J., Yu, H. & Sur, M. Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex. Science 320, 1638–1643 (2008).
Doengi, M. et al. GABA uptake-dependent Ca2+ signaling in developing olfactory bulb astrocytes. Proc. Natl Acad. Sci. USA 106, 17570–17575 (2009).
Lauritzen, M. Reading vascular changes in brain imaging: is dendritic calcium the key? Nature Rev. Neurosci. 6, 77–85 (2005).
Winship, I. R., Plaa, N. & Murphy, T. H. Rapid astrocyte calcium signals correlate with neuronal activity and onset of the hemodynamic response in vivo . J. Neurosci. 27, 6268–6272 (2007).
Mathiesen, C., Caesar, K., Akgören, N. & Lauritzen, M. Modification of activity-dependent increases of cerebral blood flow by excitatory synaptic activity and spikes in rat cerebellar cortex. J. Physiol. 512, 555–566 (1998).
Enager, P. et al. Pathway-specific variations in neurovascular and neurometabolic coupling in rat primary somatosensory cortex. J. Cereb. Blood Flow Metab. 29, 976–986 (2009).
Wang, X. et al. Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo . Nature Neurosci. 9, 816–823 (2006).
Lindauer, U., Megow, D., Schultze, J., Weber, J. R. & Dirnagl, U. Nitric oxide synthase inhibition does not affect somatosensory evoked potentials in the rat. Neurosci. Lett. 216, 207–210 (1996).
Yang, G., Chen, G., Ebner, T. J. & Iadecola, C. Nitric oxide is the predominant mediator of cerebellar hyperemia during somatosensory activation in rats. Am. J. Physiol. 277, R1760–R1770 (1999).
Caesar, K., Akgören, N., Mathiesen, C. & Lauritzen, M. Modification of activity-dependent increases in cerebellar blood flow by extracellular potassium in anaesthetized rats. J. Physiol. 520, 281–292 (1999).
Golanov, E. V. & Reis, D. J. Nitric oxide and prostanoids participate in cerebral vasodilation elicited by electrical stimulation of the rostral ventrolateral medulla. J. Cereb. Blood Flow Metab. 14, 492–502 (1994).
Hoffmeyer, H. W., Enager, P., Thomsen, K. J. & Lauritzen, M. J. Nonlinear neurovascular coupling in rat sensory cortex by activation of transcallosal fibers. J. Cereb. Blood Flow Metab. 27, 575–587 (2007).
Akgören, N., Mathiesen, C., Rubin, I. & Lauritzen, M. Laminar analysis of activity-dependent increases of CBF in rat cerebellar cortex: dependence on synaptic strength. Am. J. Physiol. 273, H1166–H1176 (1997).
Roman, R. J. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol. Rev. 82, 131–185 (2002).
Fujimoto, Y., Uno, E. & Sakuma, S. Effect of reactive oxygen and nitrogen species on cyclooygenase-1 and -2 activities. Prostaglandins Leukot. Essent. Fatty Acids 71, 335–340 (2004).
Sun, C. W., Falck, J. R., Okamoto, H., Harder, D. R. & Roman, R. J. Role of cGMP versus 20-HETE in the vasodilator response to nitric oxide in rat cerebral arteries. Am. J. Physiol. Heart Circ. Physiol. 279, H339–H350 (2000).
Stuehr, D. J., Santolini, J., Wang, Z., Wei, C. & Adak, S. Update on mechanism and catalytic regulation in the NO synthases. J. Biol. Chem. 279, 36167–36170 (2004).
Harder, D. R. et al. Identification of a putative microvascular oxygen sensor. Circ. Res. 79, 54–61 (1996).
Juránek, I., Suzuki, H. & Yamamoto, S. Purification, characterization and selective inhibition of human prostaglandin G/H synthase 1 and 2 expressed in the baculovirus system. Biochim. Biophys. Acta 1436, 509–518 (1999).
Hall, C. N. & Attwell, D. Assessing the physiological concentration and targets of nitric oxide in brain tissue. J. Physiol. 586, 3597–3615 (2008).
Caesar, K. et al. Glutamate receptor-dependent increments in lactate, glucose and oxygen metabolism evoked in rat cerebellum in vivo . J. Physiol. 586, 1337–1349 (2008).
Hamilton, N. B., Attwell, D. & Hall, C. N. Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front. Neuroenergetics 2, 5 (2010).
Shepro, D. & Morel, N. M. Pericyte physiology. FASEB J. 7, 1031–1038 (1993).
Puro, D. G. Physiology and pathobiology of the pericyte-containing retinal microvasculature: new developments. Microcirculation 14, 1–10 (2007).
Peppiatt, C. M., Howarth, C., Mobbs, P. & Attwell, D. Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700–704 (2006).
Yemişçi, M. et al. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nature Med. 15, 1031–1037 (2009). Shows that pericyte constriction decreases blood flow after stroke.
Lovick, T. A., Brown, L. A. & Key, B. J. Neurovascular relationships in hippocampal slices: physiological and anatomical studies of mechanisms underlying flow-metabolism coupling in intraparenchymal microvessels. Neuroscience 92, 47–60 (1999).
Lu, K. et al. Cerebral autoregulation and gas exchange studied using a human cardiopulmonary model. Am. J. Physiol. Heart Circ. Physiol. 286, H584–H601 (2004).
Boas, D. A., Jones, S. R., Devor, A., Huppert, T. J. & Dale, A. M. A vascular anatomical network model of the spatio-temporal response to brain activation. Neuroimage 40, 1116–1129 (2008).
Fiser, J., Chiu, C. & Weliky, M. Small modulation of ongoing cortical dynamics by sensory input during natural vision. Nature 431, 573–578 (2004).
Schölvinck, M., Howarth, C. & Attwell, D. The cortical energy needed for conscious perception. Neuroimage 40, 1460–1468 (2008).
Lin, A. L., Fox, P. T., Hardies, J., Duong, T. Q. & Gao, J. H. Nonlinear coupling between cerebral blood flow, oxygen consumption, and ATP production in human visual cortex. Proc. Natl Acad. Sci. USA 107, 8446–8451 (2010). Important quantification of the relative magnitudes of stimulus-induced changes in blood flow, O 2 use and ATP generation.
Fox, P. T., Raichle, M. E., Mintun, M. A. & Dence, C. Nonoxidative glucose consumption during focal physiologic neural activation. Science 241, 462–464 (1988).
Madsen, P. L., Cruz, N. F., Sokoloff, L. & Dienel, G. A. Cerebral oxygen/glucose ratio is low during sensory stimulation and rises above normal during recovery: excess glucose consumption during stimulation is not accounted for by lactate efflux from or accumulation in brain tissue. J. Cereb. Blood Flow Metab. 19, 393–400 (1999).
Mangia, S. et al. Metabolic and hemodynamic events after changes in neuronal activity: current hypotheses, theoretical predictions and in vivo NMR experimental findings. J. Cereb. Blood Flow Metab. 29, 441–463 (2009).
Buxton, R. B. & Frank, L. R. A model for the coupling between cerebral blood flow and oxygen metabolism during neural stimulation. J. Cereb. Blood Flow Metab. 17, 64–72 (1997).
Leithner, C. et al. Pharmacological uncoupling of activation induced increases in CBF and CMRO2 . J. Cereb. Blood Flow Metab. 30, 311–322 (2010).
Uğurbil, K. et al. Magnetic resonance studies of brain function and neurochemistry. Annu. Rev. Biomed. Eng. 2, 233–260 (2000).
Attwell, D. & Iadecola, C. The neural basis of functional brain imaging signals. Trends Neurosci. 25, 621–625 (2002).
Logothetis, N. K., Pauls, J., Augath, M., Trinath, T. & Oeltermann, A. Neurophysiological investigation of the basis of the fMRI signal. Nature 412, 1517–1531 (2001).
Markram, H., Lübke, J., Frotscher, M., Roth, A. & Sakmann, B. Physiology and anatomy of synaptic connections between thick tufted pyramidal neurones in the developing rat neocortex. J. Physiol. 500, 409–440 (1997).
Hillman, E. M. et al. Depth-resolved optical imaging and microscopy of vascular compartment dynamics during somatosensory stimulation. Neuroimage 35, 89–104 (2007).
Hall, C. N. & Garthwaite, J. What is the real physiological NO concentration in vivo? Nitric Oxide 21, 92–103 (2009).
Lauritzen, M. Pathophysiology of the migraine aura. The spreading depression theory. Brain 117, 199–210 (1994).
Fabricius, M. et al. Cortical spreading depression and peri-infarct depolarization in acutely injured human cerebral cortex. Brain 129, 778–790 (2006).
Dohmen, C. et al. Spreading depolarizations occur in human ischemic stroke with high incidence. Ann. Neurol. 63, 720–728 (2008).
Dreier, J. P. et al. Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations. Brain 129, 3224–3237 (2006).
Hansen, A. J. & Zeuthen, T. Extracellular ion concentrations during spreading depression and ischemia in the rat brain cortex. Acta Physiol. Scand. 113, 437–445 (1981).
Van Harreveld, A. & Kooiman, M. Amino acid release from the cerebral cortex during spreading depression and asphyxiation. J. Neurochem. 12, 431–439 (1965).
Barbour, B., Brew, H. & Attwell, D. Electrogenic glutamate uptake in glial cells is activated by intracellular potassium. Nature 335, 433–435 (1988).
Piilgaard, H. & Lauritzen, M. Persistent increase in oxygen consumption and impaired neurovascular coupling after spreading depression in rat neocortex. J. Cereb. Blood Flow Metab. 29, 1517–1527 (2009). Quantifies changes in energy use, blood flow and neurovascular coupling after spreading depression.
Takano, T. et al. Cortical spreading depression causes and coincides with tissue hypoxia. Nature Neurosci. 10, 754–762 (2007).
Hashemi, P. et al. Persisting depletion of brain glucose following cortical spreading depression, despite apparent hyperaemia: evidence for risk of an adverse effect of Leão's spreading depression. J. Cereb. Blood Flow Metab. 29, 166–175 (2009).
Busija, D. W., Bari, F., Domoki, F., Horiguchi, T. & Shimizu, K. Mechanisms involved in the cerebrovascular dilator effects of cortical spreading depression. Prog. Neurobiol. 86, 379–395 (2008).
Fabricius, M., Akgören, N. & Lauritzen, M. Arginine–nitric oxide pathway and cerebrovascular regulation in cortical spreading depression. Am. J. Physiol. 269, H23–H29 (1995).
Wahl, M., Schilling, L., Parsons, A. A. & Kaumann, A. Involvement of calcitonin gene-related peptide (CGRP) and nitric oxide (NO) in the pial artery dilatation elicited by cortical spreading depression. Brain Res. 637, 204–210 (1994).
Wahl, M., Lauritzen, M. & Schilling, L. Changes of cerebrovascular reactivity after cortical spreading depression in cats and rats. Brain Res. 411, 72–80 (1987).
Scheckenbach, K. E., Dreier, J. P., Dirnagl, U. & Lindauer, U. Impaired cerebrovascular reactivity after cortical spreading depression in rats: restoration by nitric oxide or cGMP. Exp. Neurol. 202, 449–455 (2006).
Ames, A. III, Wright, R. L., Kowada, M., Thurston, J. M. & Majno, G. Cerebral ischaemia. II. The no-reflow phenomenon. Am. J. Pathol. 52, 437–453 (1968).
Nelson, C. W., Wei, E. P., Povlishock, J. T., Kontos, H. A. & Moskowitz, M. A. Oxygen radicals in cerebral ischemia. Am. J. Physiol. 263, H1356–H1362 (1992).
Hauck, E. F., Apostel, S., Hoffmann, J. F., Heimann, A. & Kempski, O. Capillary flow and diameter changes during reperfusion after global cerebral ischemia studied by intravital video microscopy. J. Cereb. Blood Flow Metab. 24, 383–391 (2004).
Theilen, H., Schröck, H. & Kuschinsky, W. Gross persistence of capillary plasma perfusion after middle cerebral artery occlusion in the rat brain. J. Cereb. Blood Flow Metab. 14, 1055–1061 (1994).
Iadecola, C. & Zhang, F. Nitric oxide-dependent and -independent components of cerebrovasodilation elicited by hypercapnia. Am. J. Physiol. 266, R546–R552 (1994).
Wagerle, L. C. & Mishra, O. P. Mechanism of CO2 response in cerebral arteries of the newborn pig: role of phospholipase, cyclooxygenase, and lipoxygenase pathways. Circ. Res. 62, 1019–1026 (1988).
Kågström, E., Smith, M. L. & Siesjö, B. K. Cerebral circulatory responses to hypercapnia and hypoxia in the recovery period following complete and incomplete cerebral ischemia in the rat. Acta Physiol. Scand. 118, 281–291 (1983).
Zou, M. H., Leist, M. & Ullrich, V. Selective nitration of prostacyclin synthase and defective vasorelaxation in atherosclerotic bovine coronary arteries. Am. J. Pathol. 154, 1359–1365 (1999).
Fleming, I. Cytochrome P450 epoxygenases as EDHF synthase(s). Pharmacol. Res. 49, 525–533 (2004).
Sun, J., Druhan, L. J. & Zweier, J. L. Dose dependent effects of reactive oxygen and nitrogen species on the function of neuronal nitric oxide synthase. Arch. Biochem. Biophys. 471, 126–133 (2008).
Kaur, J., Zhao, Z., Klein, G. M., Lo, E. H. & Buchan, A. M. The neurotoxicity of tissue plasminogen activator? J. Cereb. Blood Flow Metab. 24, 945–963 (2004).
Nicole, O. et al. The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling. Nature Med. 7, 59–64 (2001).
Park, L. et al. Key role of tissue plasminogen activator in neurovascular coupling. Proc. Natl Acad. Sci. USA 105, 1073–1078 (2008). Suggests that tPA, as used clinically to clear clots from blocked vessels, has a role in neurovascular coupling.
Armstead, W. M., Cines, D. B. & Al-Roof Higazi, A. Altered NO function contributes to impairment of uPA and tPA cerebrovasodilation after brain injury. J. Neurotrauma 21, 1204–1211 (2004).
Cipolla, M. J., Lessov, N., Clark, W. M. & Haley, E. C. Jr. Postischemic attenuation of cerebral artery reactivity is increased in the presence of tissue plasminogen activator. Stroke 31, 940–945 (2000).
Johnson, N. A. et al. Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology 234, 851–859 (2005).
Ruitenberg, A. et al. Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam study. Ann. Neurol. 57, 789–794 (2005).
Park, L. et al. Aβ-induced vascular oxidative stress and attenuation of functional hyperemia in mouse somatosensory cortex. J. Cereb. Blood Flow Metab. 24, 334–342 (2004).
Kuchibhotla, K. V., Lattarulo, C. R., Hyman, B. T. & Bacskai, B. J. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323, 1211–1215 (2009).
Chow, N. et al. Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype. Proc. Natl Acad. Sci. USA 104, 823–828 (2007).
D'Esposito, M., Deouell, L. Y. & Gazzaley, A. Alterations in the BOLD fMRI signal with ageing and disease: a challenge for neuroimaging. Nature Rev. Neurosci. 4, 863–872 (2003).
Geraldes, P. et al. Activation of PKC-δ and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nature Med. 15, 1298–1306 (2009).
We apologize to those whose work we have not cited because of space constraints. We thank the following for useful discussion: K. Caesar, A. Gjedde, C. Hall, A. Mishra, G. Rees and A. Roth. Work in our laboratories is supported by the Fondation Leducq, the European Research Council, the Wellcome Trust, the UK Medical Research Council, the Dunhill Medical Trust, the Biomedical Research Centres of the UK National Institute for Health Research, the European Commission's Sixth Framework Programme, the Human Frontier Science Program, the Danish Medical Research Council, the Lundbeck Foundation, the Nordea Foundation Centre for Healthy Aging, the Novo Nordisk Foundation, the Canadian Institutes of Health Research, the Canada Research Chair in Neuroscience, and the US National Institutes of Health (National Eye Institute).
The authors declare no competing financial interests.
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Attwell, D., Buchan, A., Charpak, S. et al. Glial and neuronal control of brain blood flow. Nature 468, 232–243 (2010). https://doi.org/10.1038/nature09613
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