Review
Astrocytes and the regulation of cerebral blood flow

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Moment-to-moment changes in local neuronal activity lead to dynamic changes in cerebral blood flow. Emerging evidence implicates astrocytes as one of the key players in coordinating this neurovascular coupling. Astrocytes are poised to sense glutamatergic synaptic activity over a large spatial domain via activation of metabotropic glutamate receptors and subsequent calcium signaling and via energy-dependent glutamate transport. Astrocyte foot processes can signal vascular smooth muscle by arachidonic acid pathways involving astrocytic cytochrome P450 epoxygenase, astrocytic cyclooxygenase-1 and smooth muscle cytochrome P450 ω-hydroxylase activities, and by astrocytic and smooth muscle potassium channels. Non-glutamatergic transmitters released from neurons, such as nitric oxide, cyclooxygenase-2 metabolites and vasoactive intestinal peptide, might modulate neurovascular signaling at the level of the astrocyte or smooth muscle. Thus, astrocytes have a pivotal role in dynamic signaling within the neurovascular unit. Important questions remain on how this signaling is integrated with other pathways in health and disease.

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).

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