Trends in Neurosciences
ReviewAstrocytes and the regulation of cerebral blood flow
Introduction
Steady-state regional cerebral blood flow (CBF) is matched to regional energy metabolism. However, increases in local neuronal activity lead to dynamic increases in CBF that exceed the increases in oxidative metabolism. This relative hyperemic response provides an increased oxygen gradient between blood vessels and tissue for assuring adequate oxygen diffusion to the most distant mitochondria when oxygen demand fluctuates. Here, we focus on the role of astrocytes in coordinating the vascular response to neuronal activation.
Our understanding of the multifunctional role of astrocytes and their relationships with neurons, blood vessels and other astrocytes has grown substantially in recent years. Astrocytes are now known to have more of a spongiform appearance than stellate appearance because of the many fine processes that extend beyond the large processes that typically stain for intermediate filaments. These fine processes have minimal spatial overlap with the processes of other astrocytes and result in an individual astrocytic domain that is thought to contain 300–600 neuronal dendrites [1] and 105 synapses in the rodent cortex and hippocampus 2, 3, 4. In the human cortex, a single astrocyte might sense the activity and regulate the function of more than one million synapses within its domain [4]. Moreover, each astrocyte has at least one process with endfeet surrounding a blood vessel [5]. By contrast, processes from neurons are rarely in direct contact with intraparenchymal blood vessels. This anatomical relationship has led to the hypothesis that astrocytes have a pivotal role in the dynamic regulation of the cerebral circulation 6, 7.
Blood delivered to the major cerebral arteries is distributed over the cortical surface through pial arteries that give rise to penetrating arterioles. Pial arteries are in close proximity to the underlying glia limitans, and intraparenchymal vessels emerging from penetrating arterioles beyond the space of Virchow are in direct contact with foot processes of astrocytes. In capillaries and venules without smooth muscle, integrins maintain adhesion of foot processes with the basal lamina surrounding the endothelium and pericytes. Signaling between astrocytes and endothelium is important for angiogenesis, maintenance of endothelial tight junctions and transport across the blood–brain barrier. More recently, signaling between astrocytes and vascular smooth muscle (VSM) in intraparenchymal arterioles and between glia limitans and pial arteries has assumed increasing importance in the regulation of CBF. Changes in CBF are actively controlled by changes in VSM tone, leading to dilation or constriction of pial arteries and intraparenchymal arterioles. With widespread neuronal activation, dilation of pial arteries is coordinated with intraparenchymal dilation to help maintain a constant perfusion pressure in penetrating arterioles and prevent a passive decrease in CBF in other brain regions. This coordination is thought to depend on signaling through astrocytes [8] and possibly occur by ascending dilation propagated through the endothelium [9].
Measurements with laser-Doppler flowmetry (LDF), which measures red-blood-cell flux integrated in cortical tissue typically over ∼1 mm depth, show increases in CBF in the primary somatosensory cortex within 1–2 s of sensory stimulation [10]. Similar response times are evident with intrinsic monitoring of tissue hemoglobin concentration and with functional magnetic resonance imaging (fMRI), which uses the blood-oxygen-level-dependent signal as a surrogate for CBF coupled to neuronal activity 11, 12, 13. More recent work has employed Ca2+ imaging in brain slices and two-photon imaging in the intact brain to reveal involvement of astrocytes in the coupling of CBF with neuronal activation. One way astrocytes might monitor excitatory presynaptic activity is by glutamate activation of metabotropic glutamate (mGlu) receptors, which are known to stimulate phospholipase C and increase astrocytic Ca2+. Here, we summarize some of these recent findings that illustrate the complexity of dynamic communication between cell types within the neurovascular unit with an emphasis on signaling by arachidonic acid metabolites and the integration with other signaling pathways.
Section snippets
Cytochrome P450 epoxygenase metabolites
By the mid-1990s, several groups suggested a role for nitric oxide (NO) derived from neurons and for adenosine in contributing to vasodilation during neural activation 14, 15, 16. However, these molecules did not account for the entire vascular response [17]. In 1998, Harder et al. [7] proposed that astrocyte signaling involving epoxygenase metabolites of arachidonic acid could have an important role in neurovascular coupling. Cyclooxygenase (COX) products of arachidonic acid metabolism had
Signaling initiated by mGlu receptor activation
More direct evidence of a role for astrocytes in neurovascular coupling has relied on observations in brain slices. In vitro, astrocytes are known to propagate Ca2+ waves throughout their processes by the release of ATP through connexin hemichannels and consequent activation of purinergic receptors on their own processes and on adjacent astrocytes 40, 41, 42. Adjacent foot processes can also communicate through gap junctions and lead to the spread of signals along the vascular wall [5]. By
Potassium signaling
Astrocytes have long been known to have high permeability to K+. Indeed, maintenance of a constant level of extracellular K+ during neuronal activity is an important function of astrocytes for maintaining neuronal excitability. Early observations that astrocyte foot processes on blood vessels had a high density of K+ channels led to the hypothesis that neuronal release of K+ during action potentials resulted in the uptake of K+ by astrocyte processes at synapses that was counterbalanced by
20-Hydroxyeicosatetraenoic acid signaling
Another eicosanoid, known as 20-hydroxyeicosatetraenoic acid (20-HETE), produces depolarization of VSM at subnanomolar concentrations by closing KCa channels and opening voltage-dependent Ca2+ channels 56, 57. CYP enzymes that possess ω-hydroxylase activity generate 20-HETE from arachidonic acid. Isoforms of the CYP 4A family possess ω-hydroxylase activity and are expressed in VSM, including cerebral VSM, where they produce 20-HETE 58, 59. Interestingly, work in hippocampal slices by Mulligan
Adenosine signaling
Adenosine is a potent vasodilator and has long been implicated as a mediator of neurovascular coupling 15, 17. Indeed, adenosine A2A receptors have a role in dilation of upstream pial arterioles during neuronal activation or direct activation of glutamatergic receptors 68, 69. In addition to acting on vascular adenosine receptors, adenosine could act on astrocytes, which also express various types of adenosine receptors [70]. Activation of A2B receptors can increase intracellular Ca2+ in
Carbon monoxide signaling
Carbon monoxide (CO) derived from heme oxygenase metabolism of heme has a prominent role in various aspects of cerebrovascular regulation in the newborn pig [78]. Application of glutamate to the cortical surface of piglet brain in vivo generates CO and dilates pial arteries in a glial-dependent manner [79]. The dilation depends on activation of VSM KCa channels [80], where CO binds to a heme ligand [81]. In cortical slices from piglet brain, production of CO, activation of VSM KCa channels and
Neuronal modulation of astrocyte responses
During neuronal stimulation, NMDA receptors coupled to nNOS are activated and lead to NO production by a mechanism dependent on tissue plasminogen activator [84]. Neuronally derived NO is usually considered to directly signal the VSM. However, NO might also modulate signaling within astrocytes, although this possibility has not been well investigated. Other neurotransmitters might also interact with astrocyte signaling. In cortical slices, stimulation of vasoactive intestinal peptide
Segmental changes in vascular blood volume
The vascular volume within arterioles comprises a small fraction of the total cerebral blood volume, yet substantial changes in blood volume occur during neuronal activation. Increases in blood volume within capillaries and small venules have been reported to accompany the increase in red-blood-cell flux [11]. Because the increase in capillary and venular volume lag behind the brisk increase in arteriolar volume, the increased volume in the these downstream vessels without smooth muscle is
Astrocyte responses in vivo
Two-photon imaging has enabled a closer examination of the relationship of neuronal activation, astrocytic Ca2+ and vasodilation in the cerebral cortex of intact anesthetized animals. Photolysis of caged Ca2+ in mouse cortical astrocytes produced dilation of some of the neighboring arterioles with a latency of 1–2 s and a peak response within 4 s [93]. In contrast to some studies using brain slices, constriction was not observed in vivo. Perivascular astrocytes expressed COX-1, and the dilation
Issues to be resolved
Although the preponderance of evidence summarized before indicates a crucial role for astrocytes in the control of CBF, many questions remain to be answered.
First, vasodilation, as assessed by LDF, blood-oxygen-level-dependent signals or the intrinsic optical signal, begins to occur in <2 s from the onset of sensory stimulation, whereas the astrocytic Ca2+ response often has a delay of >2 s and a peak response that occurs a few seconds later 13, 94. Therefore, the initial vasodilation seems to
Conclusions
Emerging evidence from work in brain slices and in intact anesthetized animals indicates that astrocytes play a crucial part in gathering information on presynaptic activity integrated over a large and discrete spatial domain and in using that information to dynamically regulate local perfusion. The astrocyte signaling mechanisms are complex but seem to involve increases in astrocytic Ca2+ that are initiated by activation of the mGlu receptor, phospholipase C and Ins(1,4,5)P3 and that are
Acknowledgements
We are supported in this area of research by a grant from the National Institutes of Health (HL59996; www.nih.gov).
References (113)
Astrocytic complexity distinguishes the human brain
Trends Neurosci.
(2006)Role of nitric oxide in the coupling of cerebral blood flow to neuronal activation in rats
Neurosci. Lett.
(1993)Calcium influx factor, further evidence it is 5,6-epoxyeicosatrienoic acid
J. Biol. Chem.
(1999)Contribution of epoxyeicosatrienoic acids to the hypoxia-induced activation of Ca2+-activated K+ channel current in cultured rat hippocampal astrocytes
Neuroscience
(2006)Neurovascular relationships in hippocampal slices: physiological and anatomical studies of mechanisms underlying flow-metabolism coupling in intraparenchymal microvessels
Neuroscience
(1999)Inhibition of vasomotion in hippocampal cerebral arterioles during increases in neuronal activity
Auton. Neurosci.
(2002)Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with KIR4.1
Neuroscience
(2004)Distribution of rSlo Ca2+-activated K+ channels in rat astrocyte perivascular endfeet
Brain Res.
(2002)Ca2+-activated potassium (KCa) channel inhibition decreases neuronal activity-blood flow coupling
Brain Res.
(2002)20-Hydroxyeicosatetraenoic acid-induced vasoconstriction and inhibition of potassium current in cerebral vascular smooth muscle is dependent on activation of protein kinase C
J. Biol. Chem.
(1997)
Adenosine receptor mediated stimulation of intracellular calcium in acutely isolated astrocytes
Brain Res.
Colocalization of ATP release sites and ecto-ATPase activity at the extracellular surface of human astrocytes
J. Biol. Chem.
Brain hemodynamic changes mediated by dopamine receptors: role of the cerebral microvasculature in dopamine-mediated neurovascular coupling
Neuroimage
Coupling of neural activity to blood flow in olfactory glomeruli is mediated by astrocytic pathways
Neuron
Synaptic islands defined by the territory of a single astrocyte
J. Neurosci.
Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains
J. Neurosci.
Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury
Proc. Natl. Acad. Sci. U. S. A.
Signaling at the gliovascular interface
J. Neurosci.
Does the release of potassium from astrocyte endfeet regulate cerebral blood flow?
Science
Functional hyperemia in the brain. Hypothesis for astrocyte-derived vasodilator metabolites
Stroke
Astrocytes are a key conduit for upstream signaling of vasodilation during cerebral cortical neuronal activation in vivo
Am. J. Physiol. Heart Circ. Physiol.
Local and conducted vasomotor responses in isolated rat cerebral arterioles
Am. J. Physiol.
Interaction of nitric oxide, 20-HETE, and EETs during functional hyperemia in whisker barrel cortex
Am. J. Physiol. Heart Circ. Physiol.
Compartment-resolved imaging of activity-dependent dynamics of cortical blood volume and oximetry
J. Neurosci.
Rapid astrocyte calcium signals correlate with neuronal activity and onset of the hemodynamic response in vivo
J. Neurosci.
Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex
Science
Role of adenosine in regulation of regional cerebral blood flow in sensory cortex
Am. J. Physiol.
Importance of nitric oxide synthase inhibition to the attenuated vascular responses induced by topical l-nitroarginine during vibrissal stimulation
J. Cereb. Blood Flow Metab.
Coupling of cerebral blood flow to neuronal activation: role of adenosine and nitric oxide
Am. J. Physiol.
P-450 metabolites of arachidonic acid in the control of cardiovascular function
Physiol. Rev.
Mechanism of action of cerebral epoxyeicosatrienoic acids on cerebral arterial smooth muscle
Am. J. Physiol.
TRPV4 forms a novel Ca2+ signaling complex with ryanodine receptors and BKCa channels
Circ. Res.
Role of ADP-ribose in 11,12-EET-induced activation of KCa channels in coronary arterial smooth muscle cells
Am. J. Physiol. Heart Circ. Physiol.
Afferent arteriolar dilation to 11,12-EET analogs involves PP2A activity and Ca2+-activated K+ Channels
Microcirculation
Metabolism of arachidonic acid to epoxyeicosatrienoic acids, hydroxyeicosatetraenoic acids, and prostaglandins in cultured rat hippocampal astrocytes
J. Neurochem.
Effect of protein kinase C modulators on 14,15-epoxyeicosatrienoic acid incorporation into astroglial phospholipids
J. Neurochem.
Molecular characterization of an arachidonic acid epoxygenase in rat brain astrocytes
Stroke
Soluble epoxide hydrolase: a novel therapeutic target in stroke
J. Cereb. Blood Flow Metab.
Role of P-450 arachidonic acid expoygenase in the response of cerebral blood flow to glutamate in rats
Stroke
Dilation of cerebral arterioles by cytochrome P-450 metabolites of arachidonic acid
Am. J. Physiol.
Newborn piglet cerebral microvascular responses to epoxyeicosatrienoic acids
Am. J. Physiol.
P-450 epoxygenase and NO synthase inhibitors reduce cerebral blood flow response to N-methyl-d-aspartate
Am. J. Physiol. Heart Circ. Physiol.
Suppression of cortical functional hyperemia to vibrissal stimulation in the rat by epoxygenase inhibitors
Am. J. Physiol. Heart Circ. Physiol.
Dependency of cortical functional hyperemia to forepaw stimulation on epoxygenase and nitric oxide synthase activities in rats
J. Cereb. Blood Flow Metab.
Interaction of mechanisms involving epoxyeicosatrienoic acids, adenosine receptors, and metabotropic glutamate receptors in neurovascular coupling in rat whisker barrel cortex
J. Cereb. Blood Flow Metab.
Tone-dependent vascular responses to astrocyte-derived signals
Am. J. Physiol. Heart Circ. Physiol.
Metabotropic glutamate receptor activation enhances the activities of two types of Ca2+-activated K+ channels in rat hippocampal astrocytes
J. Neurosci.
Hypoxic preconditioning and tolerance via hypoxia inducible factor (HIF) 1α-linked induction of P450 2C11 epoxygenase in astrocytes
J. Cereb. Blood Flow Metab.
Neuroprotection and P450 2C11 upregulation after experimental transient ischemic attack
Stroke
Direct observation of calcium-independent intercellular ATP signaling in astrocytes
Anal. Chem.
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