J Appl Physiol 100: 328 –335, 2006; doi:10.1152/japplphysiol.00966.2005.
Invited Review
HIGHLIGHTED TOPIC
Regulation of the Cerebral Circulation
Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease Helene Girouard and Costantino Iadecola Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York Girouard, Helene, and Costantino Iadecola. Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol 100: 328 –335, 2006; doi: 10.1152/japplphysiol.00966.2005.—The brain is critically dependent on a continuous supply of blood to function. Therefore, the cerebral vasculature is endowed with neurovascular control mechanisms that assure that the blood supply of the brain is commensurate to the energy needs of its cellular constituents. The regulation of cerebral blood flow (CBF) during brain activity involves the coordinated interaction of neurons, glia, and vascular cells. Thus, whereas neurons and glia generate the signals initiating the vasodilation, endothelial cells, pericytes, and smooth muscle cells act in concert to transduce these signals into carefully orchestrated vascular changes that lead to CBF increases focused to the activated area and temporally linked to the period of activation. Neurovascular coupling is disrupted in pathological conditions, such as hypertension, Alzheimer disease, and ischemic stroke. Consequently, CBF is no longer matched to the metabolic requirements of the tissue. This cerebrovascular dysregulation is mediated in large part by the deleterious action of reactive oxygen species on cerebral blood vessels. A major source of cerebral vascular radicals in models of hypertension and Alzheimer disease is the enzyme NADPH oxidase. These findings, collectively, highlight the importance of neurovascular coupling to the health of the normal brain and suggest a therapeutic target for improving brain function in pathologies associated with cerebrovascular dysfunction. cerebral blood flow; astrocytes; NADPH oxidase; free radicals
A LARGE BODY OF EVIDENCE INDICATES that neural activity is closely related to cerebral blood flow (CBF). The close spatial and temporal relationship between neural activity and CBF, termed neurovascular coupling, is at the basis of modern neuroimaging techniques that utilize the cerebrovascular changes induced by activation to map regional changes in function in the behaving human brain. However, in several brain pathologies, the interaction between neural activity and cerebral blood vessels is disrupted, and the resulting homeostatic unbalance may contribute to brain dysfunction. This review provides a brief summary of neurovascular coupling in the normal state and in diseases including hypertension, ischemic stroke, and Alzheimer disease (AD).
NEUROVASCULAR COUPLING IN THE NORMAL STATE
Cerebral blood vessels have many unique structural and functional characteristics that differentiate them from vessels in other organs. Perhaps the most distinctive feature of cerebral blood vessels is their close interaction with neurons and glia. A growing body of evidence indicates that neurons, glia (astrocytes, microglia, oligodendrocytes), and vascular cells (endoAddress for reprint requests and other correspondence: C. Iadecola, Division of Neurobiology, 411 East 69th St., Rm. KB410, New York, NY 10021 (e-mail:
[email protected]). 328
thelium, smooth muscle cells or pericytes, adventitial cells) are closely related developmentally, structurally, and functionally. The term “neurovascular unit” was introduced to highlight the intimate functional relationships between these cells and their coordinated pattern of reaction to injury (see Ref. 31 for references). The increase in CBF produced by brain activity, or functional hyperemia, is an example of the close interaction between neurons, glia, and vascular cells. In the next sections, we will describe the anatomical and functional bases of neurovascular coupling in the normal brain. Cerebral Blood Vessels Large cerebral arteries arising from the circle of Willis branch out into smaller pial arteries and arterioles that travel on the surface of the brain across the subarachnoid space. Pial arteries give rise to penetrating arteries and arterioles that enter into the substance of the brain. These arteries consist of an endothelial cell layer, a smooth muscle cell layer, and an outer layer, termed adventitia, containing collagen, fibroblasts, and perivascular nerves (68) (Fig. 1). Penetrating vessels are separated from the brain by the Virchow-Robin space, which contains cerebrospinal fluid. On the outer side of the VirchowRobin space, astrocytes give rise to the glia limitans membrane. As the arterioles penetrate deeper into the brain, the Virchow-Robin space disappears and the vascular basement
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Fig. 1. Relationship of cerebrovascular cells with neurons, glia, and perivascular nerves. Pial arteries and arterioles are innervated by nerve fibers arising from cranial autonomic ganglia. Smaller cerebral arterioles (⬍100 m) come in contact with nerve terminals arising from local interneurons and from central pathways originating from distant sites in the brain stem or basal forebrain. These neurovascular associations often terminate on astrocytic end feet lining the abluminal vascular surface. Pericytes, contractile cells embedded in the capillary wall, are closely associated with astrocytic end feet and endothelial cells. The term “neurovascular unit” has been coined to define the close structural and functional relationships between brain cells and vascular cells. In diseases states, such as ischemic stroke, Alzheimer disease, and hypertension, the function of the neurovascular unit is profoundly disrupted resulting in alterations in cerebrovascular reactivity that compromise brain function.
membrane enters into direct contact with the astrocytic end feet. Arterioles become progressively smaller, lose the smooth muscle cell layer, and become cerebral capillaries. The density of brain capillaries within the brain is regionally heterogeneous and varies according to regional blood flow and regional metabolic demands (81). Capillaries consist of endothelial cells, pericytes, and the capillary basal lamina on which astrocytic feet are attached (68) (Fig. 1). Brain endothelial cells are unique in that they are not fenestrated and are sealed by tight junctions, features that underlie the blood-brain barrier. Endothelial cells play an important role in the regulation of vascular tone by releasing potent vasoactive factors, such as nitric oxide (NO), free radicals, prostacyclin, endothelium-derived hyperpolarizing factor, and endothelin (19). Pericytes have contractile properties and may modulate capillary diameter (31). Perivascular astrocytes surround most of the capillary abluminal surface with their end feet. There is close association between cerebral arteries, arterioles, and capillaries with nerves originating from central and peripheral sources (Fig. 1). These relationships are addressed elsewhere in this series (see Ref. 25a).
muscle cells (20, 54), leading to their hyperpolarization and subsequent relaxation. During sustained activation, ATP depletion could lead to opening of ATP-sensitive K⫹ channels (KATP) on vessels. Therefore, KATP channels have been implicated in the mechanisms of neurovascular coupling (54). Furthermore, KATP could also participate in neurovascular coupling by mediating the vasodilation produced by agents that increase cAMP, such as adenosine or prostacyclin (20). The vasodilatatory effect of increased concentrations of H⫹ is also mediated, at least in part, by the opening of K⫹ channels (20). It has also been suggested that activity-induced reductions in extracellular Ca2⫹ may produce vasodilation (28). Vasoactive factors related to energy metabolism. The brain has little energy reserve and requires a continuous supply of glucose and O2 through CBF. A sudden increase in the demand Table 1. Factors implicated in neurovascular coupling Agent
Vasoactive ions K⫹ H⫹ Ca2⫹ Metabolic factors Lactate, CO2 Hypoxia Adenosine Vasoactive neurotransmitters Dopamine GABA Acetylcholine Vasoactive intestinal peptide Other NO COX-2 products P450 products CO
Mechanisms of Neurovascular Coupling: The Quest for the Mediators The mechanisms underlying neurovascular coupling have been the subject of enquiry for more than a century (31), and numerous vasoactive factors have been implicated in neurovascular coupling (Table 1). These include ions, metabolic by-products, vasoactive neurotransmitters, and vasoactive factors released in response to neurotransmitters. Vasoactive ions. K⫹ and H⫹ are generated by the extracellular ionic currents induced by action potentials and synaptic transmission. Elevations in extracellular K⫹ up to 8 –10 mM cause dilation of arterioles both in vitro and in vivo (45, 54). This effect is mediated by the opening of K⫹ channels, mainly of the inward rectifier type, on the membrane of arterial smooth J Appl Physiol • VOL
References
45 45 28 71, 73 73 72 43 22 74 83 61 55 67 51
NO, nitric oxide; COX-2, cyclooxygenase-2; CO, carbon monoxide.
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for energy during synaptic activity could result in a relative lack of O2 and glucose, which may be a factor in triggering the hemodynamic response (3). However, the reduction in brain O2 concentration at the site of activation is small and transient and cannot account for sustained increases in flow (2). Furthermore, the CBF response to activation is not altered by hypoglycemia or hypoxia, suggesting that lack of glucose or O2 is not the primary factor triggering vasodilation (3). On the other hand, adenosine, a potent vasodilator produced during ATP catabolism, is involved in neurovascular coupling in cerebellum (47) and cerebral cortex (41). Lactate produced during brain activation could also be an important mediator of functional hyperemia by increasing H⫹ concentration and producing vasodilation (3). Pellerin and colleagues (66) hypothesized that astrocytes metabolize glucose through glycolysis, leading to lactate production. Lactate, in turn, is taken up by neurons and used as fuel for ATP synthesis. Recent data in hippocampal slices support this theory. Using two-photon confocal microscopy of NADH fluorescence, Kasischke et al. (38) have investigated the spatial and temporal characteristics of energy metabolism in neurons and astrocytes during activation. They provided evidence of an early NADH decrease in neurons, reflecting oxidative metabolism, followed by a NADH increase in astrocytes, reflecting glycolytic metabolism (38). These observations are consistent with the hypothesis that neuronal oxidative metabolism precedes glial glycolysis and fit well with the reduction in tissue O2 (“dip”) observed at the onset of activation with optical imaging, functional MRI, and O2 electrodes (2). However, the data of Kasischke et al. do not shed light on the role of lactate in the vasodilation produced by neural activation. Rather, the lactate rise is small and transient, and it cannot account in full for the increase in flow produced by neural activity (3). Central pathways, interneurons, and vasoactive neurotransmitters. It has long been proposed that vasoactive neurotransmitters released during neural activity contribute to the vasodilation (Table 1). These neurotransmitters could be released from neurovascular projections that terminate close to blood vessels originating from local interneurons or from distant nuclei and modulate CBF (Fig. 1). However, the contribution of the vascular innervation to functional hyperemia has not been firmly established. The role of interneurons has recently been addressed by Cauli et al. (8), who, using forebrain slices, have been able to show that activation of interneurons with neurovascular contacts produces vasodilation. Furthermore, in cerebellum the CBF response evoked by somatosensory activation is decreased in cyclin D2-null mice, which lack stellate interneurons in the cerebellar molecular layer (84). These data implicate specific classes of interneurons in the regulation of the cerebral microcirculation during neural activity (see also Ref. 25a). Other vasoactive factors released by neural activity. Vasoactive factors can also be generated by the intracellular signaling induced by activation of neurotransmitter receptors. For example, activation of glutamate receptors produces vasodilation and increases blood flow. In neocortex and hippocampus, exogenous glutamate or N-methyl-D-aspartate (NMDA) dilates pial arterioles and/or cerebral microvessels (18, 49). Functional hyperemia in cerebral and cerebellar cortex is inhibited by DL-␣-amino-3-hydroxy-5-methylisoxazolepropionic acid (CAMPA) and/or NMDA receptor blockers (1, J Appl Physiol • VOL
33, 62). Because glutamate is not vasoactive in isolated cerebral arteries (18), the vasodilation is mediated by vasoactive factors whose synthesis is triggered by the changes in intracellular Ca2⫹ associated with glutamate receptor activation. The increase in Ca2⫹ activates Ca2⫹-dependent enzymes that produce potent vasodilators. One such enzyme is the neuronal isoform of NO synthase (nNOS), which produces the vasodilator NO. The vasodilation produced by topical application of NMDA or glutamate is reduced by nNOS inhibitors (18, 85). There is ample evidence that NO contributes to the increase in CBF produced by functional activity. Thus the increase in CBF in the somatosensory cortex induced by sensory stimulation is associated with NO release and is attenuated by nNOS inhibitors (5, 48, 61). However, in cerebral cortex, the effect of NO synthase inhibition on functional hyperemia can be reversed by application of exogenous NO. This finding suggests that the presence of NO is required for the vasodilation, but that NO is not the ultimate mediator of smooth muscle relaxation (48). NO is also involved in the increase in CBF induced by activation of the cerebellar cortex (1, 33). However, at variance with the cerebral cortex, in cerebellum the attenuation of the CBF response cannot be reversed by NO donors and is observed also in nNOS null mice (86, 87). These findings suggest that, in cerebellum, NO plays an obligatory role in the mechanisms of the vasodilation. The increase in intracellular Ca2⫹ evoked by glutamate also activates phospholipase A2, leading to production of arachidonic acid. Arachidonic acid is then metabolized by the cyclooxygenase (COX) pathway, producing vasodilatatory prostaglandins (25). Although there are several isoforms of COX (COX-1, -2, and -3) (25), COX-2 is the main isoform involved in functional hyperemia. COX-2 is present in axon terminals and dendritic processes separated from penetrating arterioles and capillaries by glial processes (80). Functionally, the CBF increase evoked by somatosensory stimulation is attenuated by COX-2 inhibitors or in COX-2 null mice, whereas COX-1 does not participate in the response (55, 57). The COX-2 metabolites responsible for the vasodilation are likely to involve vasodilatatory prostaglandins. Other arachidonic acid products that are involved in functional hyperemia include metabolites of the p450 pathway, such as epoxyeicosatrienoic acids (67). Furthermore, carbon monoxide has also been proposed to contribute to functional hyperemia (51). Epoxyeicosatrienoic acids and carbon monoxide are addressed elsewhere in this series (see Leffler CW, Parfenova H, Jaggar JH, and Wang R, unpublished review and Koehler RC, Gebremedhin D, and Harder DH, unpublished review). Neurovascular Coupling: Role of Astrocytes Astrocytes are uniquely positioned to contribute to the increase in CBF produced by activation (see Koehler RC, Gebremedhin D, and Harder DH, unpublished review). Paulson and Newman (65) provided theoretical evidence that astrocytes could participate in functional hyperemia by shunting K⫹ ions, which are vasoactive, from the synapses to the astrocytic end feet surrounding blood vessels. However, this theory remains to be proven experimentally. More direct evidence for a role of astrocytes has been provided by Zonta et al. (90) in brain slices. These investigators showed that glutamate released by neural activity activates metabotropic glutamate receptors in cortical
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astrocytes, leading to increases in intracellular Ca2⫹, COX activation, and local vasodilation (90). A critical role for Ca2⫹ fluxes from neurons to astrocytes and arterioles is also supported by another study in brain slices (23). Arterioles at rest exhibit periodic contractions and relaxations, called vasomotion, a phenomenon resulting from Ca2⫹ oscillations in smooth muscle cells (23). It was found that electrical stimulation of brain slices induces Ca2⫹ waves in astrocytes, which then propagate to arterioles and inhibit vasomotion (23). The inhibition of vasomotion would allow the arteriole to be more relaxed and, presumably, increase flow. In contrast, Mulligan and MacVicar (52) demonstrated that release of caged Ca2⫹ in hippocampal astrocytes produces vasoconstriction, a response mediated by the cytochrome p450 metabolites 20-HETEs. The discrepancy between the studies of Zonta et al. and Mulligan and MacVicar is perhaps due to differences in the experimental conditions. For example, Zonta et al. preconstricted the vessels with a NO synthase inhibitor. A major limitation of studies in brain slices is the lack of cerebral perfusion. Changes in vessel diameter under these conditions are difficult to assess because the vessels lack the intrinsic smooth muscle tone provided by intravascular pressure (myogenic tone) and are not subjected to shear stress, which has profound effects on endothelial cell function (44). Nevertheless, these studies are noteworthy because they provide evidence that activity-induced Ca2⫹ transients in astrocytes are linked to changes in cerebrovascular tone. Neurovascular Coupling: Local vs. Remote Vasodilation In brain, flow is controlled by pial arteries, which are the major site of vascular resistance (27). Consequently, to optimize perfusion, the dilation of intracerebral vessels at the site of activation must be associated with dilation of upstream pial arteries (32). Additional vascular adjustments are needed to increase flow in the activated area, but not in inactive regions vascularized by other branches of the same pial artery. The mechanisms responsible for this complex and coordinated chain of events have not been completely elucidated, but several factors have emerged. The dilation initiated by active neurons may be propagated retrogradely to pial arterioles through an intrinsic mechanism such as the retrograde vasodilation of Duling and Berne (75). Indeed, retrograde vasodilation in response to ATP has been observed in isolated rat cerebral arterioles (12), whereas upstream vasodilation has been demonstrated in cerebellar cortex arterioles during activation of the parallel fibers (34). In systemic vessels, the cellular mechanisms by which the vasodilation is transmitted upstream involves intercellular conduction of signals between endothelial cells and/or vascular smooth muscle cells via gap junctions (75). The increase in shear stress on the endothelium of the feeding vessels could contribute to propagate the response further upstream (flow-mediated vasodilation) (32), but there is limited evidence supporting this possibility in the neocortical microcirculation. Less clear are the mechanisms by which the vasodilation is restricted only to the arterial branches supplying the activated areas. One possibility is that the upstream dilatation leads to increased transmural pressure in nondilated downstream branches supplying nonactivated areas inducing a myogenic response that constricts the vessels and maintains CBF constant. It is unlikely that release of vasodiJ Appl Physiol • VOL
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lator substances from the glia limitans adjacent to upstream pial arteries plays a role in remote vasodilation because flushing the brain surface with artificial cerebrospinal fluid does not attenuate the pial vasodilation induced by activation (53). Irrespective of the cellular mechanisms of the retrograde propagation of the vasodilatatory signals, vascular cells play a key role in the expression of functional hyperemia by coordinating a complex hemodynamic response that, in the end, results in focused and timely increase in CBF to the activated area. Mechanisms of Neurovascular Coupling: an Integrated View For many decades, investigators believed that functional hyperemia was the result of the action of a single vasoactive agent reaching local blood vessels by simple diffusion and producing the vasodilation (32). However, as discussed in the previous section, this view is no longer tenable. Active neurons and glia release a multitude of vasoactive factors that act in concert to increase CBF (31). Cerebral endothelial cells, pericytes, and smooth muscle cells are the target of these signals and transduce them into coordinated vascular adjustments that ultimately lead to an increase in CBF. Therefore, the increase in flow evoked by brain activity is mediated by the concerted action of multiple mediators that originate from different cells and act at different levels of the cerebral vasculature. NEUROVASCULAR COUPLING IN DISEASE
The relationship between neural activity and CBF is altered in several pathologies. These alterations perturb the delivery of substrates to active brain cells and impair the removal of potentially deleterious by-products of cerebral metabolism. The ensuing disruption of the cerebral microenvironment is likely to contribute to brain dysfunction. In this section, we will focus on the cerebrovascular dysfunction that occurs in hypertension, AD, and ischemic stroke (Table 2). Hypertension Hypertension exerts deleterious actions on the brain and its circulation. Hypertension alters the structure of cerebral blood vessels by producing vascular hypertrophy and remodeling and by promoting atherosclerosis in large cerebral arteries and lipohyalinosis in penetrating arterioles (11, 17). These structural alterations facilitate vascular occlusions and compromise cerebral perfusion. In addition, hypertension impairs the function of cerebral blood vessels (17, 27). Hypertension impairs endothelium-dependent relaxation (19) and alters cerebrovascular autoregulation (27), defined as the ability of the cerebral circulation to maintain relatively constant CBF in the face of changes in arterial pressure within a certain range. Recent evidence suggests that hypertension also alters neurovascular coupling. Administration of ANG II to mice increases arterial pressure (20 –30 mmHg) and attenuates the increase in somatosensory cortex CBF produced by whisker stimulation (⫺65%), without reducing resting CBF (40). The effects of ANG II on neurovascular coupling are blocked by losartan, indicating that they are mediated by AT1 receptors (40). The attenuation in functional hyperemia is observed even if the increase in arterial pressure is prevented by removal of a small amount of arterial blood, or if the pressor effect of ANG II is avoided by applying the peptide directly to the cerebral cortex (40). Furthermore, elevation of arterial pressure by phenylephrine administration
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Table 2. Alterations in functional hyperemia in Alzheimer disease, cerebrovascular diseases, and hypertension: selected human studies Pathology
Method for CBF Detection
Activation Task
Effect on Cortical Hemodynamic Change
Reference
Middle temporal Parietal, frontal Dorsolateral Prefrontal Mid and posterior inferior temporal
50 29 82 77 4 42 69
Alzheimer disease and APOE genotype PET PET and NIRS Xenon-133 fMRI fMRI
2 2 2 2 2
Alzheimer disease Alzheimer disease Alzheimer disease APOEε4 carriers APOEε4 carriers
Visual stimulus Verbal task Verbal task Visual naming and letter task Memory tasks
Ischemic stroke with full recovery Lacunar stroke
Hand grip Finger tapping
fMRI fMRI
Extra- and intracranial stenosis
Hand grip
fMRI
Common carotid or vertebral artery occlusion Internal carotid or middle cerebral artery occlusion Essential hypertension
Finger tapping
fMRI
2 Left hippocampus 2 Somatosensory cortex, supplementary motor area 2 Somatosensory cortex, supplementary motor area 2 Supplementary motor area
Bimanual motor tasks
PET
No change in somatosensory cortex
36
Memory task
PET
2 Posterior parietal
37
Cerebrovascular diseases
26 70
CBF, cerebral blood flow; PET, positron emission tomography; NIRS: near-infrared spectroscopy; fMRI, functional magnetic resonance imaging; 2, attenuation of the CBF increase.
does not reproduce the effects of ANG II on functional hyperemia. Although these observations suggest that the cerebrovascular effect of short-term administration of ANG II is independent of the increase in arterial pressure, they do not rule out that in chronic models of hypertension, mediated by either ANG II or other factors, the elevation of arterial pressure plays a role in the cerebrovascular pathology. There is evidence that hypertension alters functional hyperemia also in humans (Table 2). The increase in CBF in posterior parietal and thalamic areas produced by cognitive tasks is reduced in patients with chronic untreated hypertension relative to normotensive individuals (37). The attenuated CBF response was associated with a lower cognitive performance (37). Reduction in resting CBF in hypertensive subjects have also been reported (24), but not by all studies (37, 46). Although confounding effects of coexisting brain pathologies cannot be ruled out, these findings provide evidence that hypertension impairs neurovascular function also in humans. Alzheimer Disease Alzheimer disease (AD) is the most common form of dementia and is characterized by deposition of amyloid -peptide (A) in the neuropil (neuritic plaques) and blood vessels (amyloid angiopathy), and by accumulation of hyperphosphorylated neurofilament in neurons (neurofibrillary tangles) (76). Cerebrovascular structure is profoundly altered in AD (21). Cerebral microvessels are reduced in number, endothelial cells are flattened, and smooth muscle cells undergo degeneration (21). Cerebrovascular function is also altered in AD (31). Resting CBF is reduced and the increase in CBF produced by activation is attenuated (Table 2). The cerebrovascular dysfunction often precedes the onset of cognitive impairment, suggesting a role in the mechanisms of the dementia (31). Mouse models of AD, in which mutated amyloid precursor protein (APP) is overexpressed to increase A levels, have a profound dysregulation of the cerebral circulation (31). Whereas endothelium-dependent responses are attenuated, reJ Appl Physiol • VOL
sponses to vasoconstrictors are exaggerated (35, 59). Functional hyperemia is impaired and cerebrovascular autoregulation is nearly abolished (58, 60). These cerebrovascular effects are present in the absence of plaques or vascular amyloid (58, 63). The cerebrovascular dysfunction observed in APP mice can be reproduced in normal mice by topical superfusion of A1– 40 on the neocortex (56, 63). Furthermore, alterations in vascular reactivity can also be observed in isolated vessels of normal mice exposed to A1– 40 (9, 59). In APP mice, the deleterious vascular effects of A worsen cerebral ischemia and enhance the ensuing brain damage (88). How do these cerebrovascular alterations contribute to the brain dysfunction? The reduced cerebral perfusion can promote ischemic lesions, which act synergistically with A to exacerbate the dementia (31). Furthermore, insufficient CBF may alter A trafficking across the blood-brain barrier (89). Therefore, reduced CBF may slow down A clearance and promote its accumulation in the brain. In addition, the CBF reduction may attenuate cerebral protein synthesis, which is essential for normal cognition (31). Thus the structural and functional alterations of the microvasculature in AD could contribute to the mechanisms of the brain dysfunction underlying the dementia. Ischemic Stroke Focal or global cerebral ischemia exerts profound effects on the normal regulation of the cerebral circulation (30). In focal cerebral ischemia, the flow reduction resulting from the arterial occlusion is greatest in the center of the ischemic territory (ischemic core) and less pronounced at the periphery (ischemic penumbra) (30). In global ischemia, the perfusion of the entire brain is interrupted, usually because of cardiac arrest. In both focal and global ischemia, when perfusion is reestablished there is a transient increase in flow (postischemic hyperemia) followed by a period of reduced flow (postischemic hypoperfusion). After ischemia, the cerebral circulation is in a state of vasoparalysis (30). After ischemic stroke in patients, the reac-
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tivity of the cerebral circulation to vasomotor stimuli is altered, autoregulation is impaired, and the increase in CBF produced by functional activation is decreased (30). Studies in which indexes of neural activity were measured have suggested that the reduction in the CBF response to activation is secondary to a reduction of the neural activity driving the hemodynamic response (6). Thus, in a rat global ischemia model, the reduction in the CBF response to cortical electrical stimulation is associated with a reduction in the amplitude of the oxidative response (oxidation of cytochrome a) evoked by activation (14). Similarly, the increase in cerebral glucose utilization evoked by stimulation of the rat whiskers after transient global ischemia is severely depressed 1 day after ischemia (13). Therefore, after focal and global ischemia, both CBF and metabolic responses are depressed even in intact regions.
probe into the functional relationship among these cells without disruption of their natural working environment. Recently introduced in vivo imaging technologies, such as two-photon confocal microscopy, may provide the opportunity to shed light on these complex relationships. In disease states, vascular dysregulation may act synergistically with other pathologies to aggravate the intensity of the insult. It would be important to gain insight into these synergistic interactions to determine the extent to which the deleterious effects of vascular dysregulation contribute to the overall brain dysfunction. Vascular dysregulation may prove to be a valuable therapeutic target in a wide variety of brain diseases.
Vascular Oxidative Stress: a Final Common Pathway to Cerebrovascular Dysfunction
GRANTS
There is accumulating evidence that vascular oxidative stress leads to profound alterations in cerebrovascular regulation (16). Hypertension, AD, and cerebral ischemia are associated with evidence of oxidative stress in cerebral blood vessels (10, 31, 78). Thus it is likely that vascular oxidative stress is responsible for the cerebrovascular alterations observed in these conditions. There is ample evidence that ANG II-induced experimental hypertension, as well as hypertension in humans, is associated with vascular oxidative stress (15). Furthermore, studies in APP mice have shown that there is free radical production in cerebral vessels at a time when there is no evidence of oxidative stress in the brain parenchyma (63). Antioxidants attenuate the cerebrovascular dysfunction in models of ANG II-induced hypertension and in APP mice, whereas transgenic mice overexpressing the free radical scavenging enzyme SOD are protected from the dysregulation (35, 39, 63). Because an increase in reactive oxygen species (ROS) generation has been demonstrated in cerebral ischemia (78), it is conceivable that the mechanisms responsible for an impaired functional hyperemia after ischemia are similar to those observed in hypertension and AD. Indeed, ROS scavengers ameliorate the disturbance in CBF produced by ischemiareperfusion (30, 78), but it is not known whether ROS scavengers improve the alteration in neurovascular coupling. ROS are produced by several enzymatic systems (78), but recent findings have identified NADPH oxidase as a major source of ROS at the vascular level (7). Inhibition of NADPH oxidase attenuates the ROS production in models of hypertension and AD, whereas mice lacking the catalytic subunit of the enzyme (gp91phox) are protected from the deleterious cerebrovascular effects of hypertension or A (39, 64). Mice lacking gp91phox have reduced brain damage after middle cerebral artery occlusion (79). Therefore, NADPH oxidase-derived ROS could also play a role in postischemic cerebrovascular dysregulation. FUTURE DIRECTIONS
As discussed above, the mechanisms of the regulation of CBF during brain activity involve the coordinated interaction of neurons, glia, and vascular cells. However, the molecular nature of these highly complex processes has not been elucidated in sufficient detail. New and powerful tools are needed to J Appl Physiol • VOL
ACKNOWLEDGMENTS We thank Dr. Carrie Drake for comments.
This research was supported by National Institutes of Health Grants HL-18974 and NS-37853. REFERENCES 1. Akgoren N, Fabricius M, and 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. 2. Ances BM. Coupling of changes in cerebral blood flow with neural activity: what must initially dip must come back up. J Cereb Blood Flow Metab 24: 1– 6, 2004. 3. Attwell D and Iadecola C. The neural basis of functional brain imaging signals. Trends Neurosci 25: 621– 625, 2002. 4. Bookheimer SY, Strojwas MH, Cohen MS, Saunders AM, PericakVance MA, Mazziotta JC, and Small GW. Patterns of brain activation in people at risk for Alzheimer’s disease. N Engl J Med 343: 450 – 456, 2000. 5. Buerk DG, Ances BM, Greenberg JH, and Detre JA. Temporal dynamics of brain tissue nitric oxide during functional forepaw stimulation in rats. Neuroimage 18: 1–9, 2003. 6. Bundo M, Inao S, Nakamura A, Kato T, Ito K, Tadokoro M, Kabeya R, Sugimoto T, Kajita Y, and Yoshida J. Changes of neural activity correlate with the severity of cortical ischemia in patients with unilateral major cerebral artery occlusion. Stroke 33: 61– 66, 2002. 7. Cai H, Griendling KK, and Harrison DG. The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci 24: 471– 478, 2003. 8. Cauli B, Tong XK, Rancillac A, Serluca N, Lambolez B, Rossier J, and Hamel E. Cortical GABA interneurons in neurovascular coupling: relays for subcortical vasoactive pathways. J Neurosci 24: 8940 – 8949, 2004. 9. Crawford F, Suo Z, Fang C, and Mullan M. Characteristics of the in vitro vasoactivity of beta-amyloid peptides. Exp Neurol 150: 159 –168, 1998. 10. De Champlain J, Wu R, Girouard H, Karas M, El Midaoui A, Laplante MA, and Wu L. Oxidative stress in hypertension. Clin Exp Hypertens 26: 593– 601, 2004. 11. Dickinson CJ. Why are strokes related to hypertension? Classic studies and hypotheses revisited. J Hypertens 19: 1515–1521, 2001. 12. Dietrich HH, Kajita Y, and Dacey RG Jr. Local and conducted vasomotor responses in isolated rat cerebral arterioles. Am J Physiol Heart Circ Physiol 271: H1109 –H1116, 1996. 13. Dietrich WD, Ginsberg MD, and Busto R. Effect of transient cerebral ischemia on metabolic activation of a somatosensory circuit. J Cereb Blood Flow Metab 6: 405– 413, 1986. 14. Duckrow RB, LaManna JS, and Rosenthal M. Disparate recovery of resting and stimulated oxidative metabolism following transient ischemia. Stroke 12: 677– 686, 1981. 15. Escobales N and Crespo MJ. Oxidative-nitrosative stress in hypertension. Curr Vasc Pharmacol 3: 231–246, 2005. 16. Faraci FM. Oxidative stress: the curse that underlies cerebral vascular dysfunction? Stroke 36: 186 –188, 2005. 17. Faraci FM, Baumbach GL, and Heistad DD. Cerebral circulation: humoral regulation and effects of chronic hypertension. J Am Soc Nephrol 1: 53–57, 1990.
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Invited Review 334
NEUROVASCULAR COUPLING
18. Faraci FM and Breese KR. Nitric oxide mediates vasodilation in response to activation of N-methyl-D-aspartate receptors in brain. Circ Res 72: 476 – 480, 1993. 19. Faraci FM and Heistad DD. Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiol Rev 78: 53–97, 1998. 20. Faraci FM and Sobey CG. Role of potassium channels in regulation of cerebral vascular tone. J Cereb Blood Flow Metab 18: 1047–1063, 1998. 21. Farkas E and Luiten PG. Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog Neurobiol 64: 575– 611, 2001. 22. Fergus A and Lee KS. GABAergic regulation of cerebral microvascular tone in the rat. J Cereb Blood Flow Metab 17: 992–1003, 1997. 23. Filosa JA, Bonev AD, and Nelson MT. Calcium dynamics in cortical astrocytes and arterioles during neurovascular coupling. Circ Res 95: e73– e81, 2004. 24. Fujishima M, Ibayashi S, Fujii K, and Mori S. Cerebral blood flow and brain function in hypertension. Hypertens Res 18: 111–117, 1995. 25. Garavito RM and Mulichak AM. The structure of mammalian cyclooxygenases. Annu Rev Biophys Biomol Struct 32: 183–206, 2003. 25a.Hamel E. Perivascular nerves and the regulation of cerebrovascular tone. J Appl Physiol. In press. 26. Hamzei F, Knab R, Weiller C, and Rother J. The influence of extra- and intracranial artery disease on the BOLD signal in FMRI. Neuroimage 20: 1393–1399, 2003. 27. Heistad DD and Kontos HA. Cerebral circulation. In: Handbook of Physiology. The Cardiovascular System. Circulation and Organ Blood Flow. Bethesda, MD: Am. Physiol. Soc., 1983, sect. 2, vol. III, pt. 1, chapt. 5, p. 137–182. 28. Heuser D. The significance of cortical extracellular H⫹, K⫹ and Ca2⫹ activities for regulation of local cerebral blood flow under conditions of enhanced neuronal activity. In: Cerebral Vascular Smooth Muscle and Its Control, edited by Elliot K and O’Connor M. New York: Elsevier, 1978, p. 339 –353. 29. Hock C, Villringer K, Muller-Spahn F, Wenzel R, Heekeren H, Schuh-Hofer S, Hofmann M, Minoshima S, Schwaiger M, Dirnagl U, and Villringer A. Decrease in parietal cerebral hemoglobin oxygenation during performance of a verbal fluency task in patients with Alzheimer’s disease monitored by means of near-infrared spectroscopy (NIRS)— correlation with simultaneous rCBF-PET measurements. Brain Res 755: 293–303, 1997. 30. Iadecola C. Cerebral circulatory dysregulation in ischemia. In: Cerebrovascular Diseases, edited by Ginsberg M and Bogousslavsky J. Cambridge, UK: Blackwell, 1998, p. 319 –332. 31. Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5: 347–360, 2004. 32. Iadecola C. Regulation of the cerebral microcirculation during neural activity: is nitric oxide the missing link? Trends Neurosci 16: 206 –214, 1993. 33. Iadecola C, Li J, Ebner TJ, and Xu X. Nitric oxide contributes to functional hyperemia in cerebellar cortex. Am J Physiol Regul Integr Comp Physiol 268: R1153–R1162, 1995. 34. Iadecola C, Yang G, Ebner TJ, and Chen G. Local and propagated vascular responses evoked by focal synaptic activity in cerebellar cortex. J Neurophysiol 78: 651– 659, 1997. 35. Iadecola C, Zhang F, Niwa K, Eckman C, Turner SK, Fischer E, Younkin S, Borchelt DR, Hsiao KK, and Carlson GA. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat Neurosci 2: 157–161, 1999. 36. Inao S, Tadokoro M, Nishino M, Mizutani N, Terada K, Bundo M, Kuchiwaki H, and Yoshida J. Neural activation of the brain with hemodynamic insufficiency. J Cereb Blood Flow Metab 18: 960 –967, 1998. 37. Jennings JR, Muldoon MF, Ryan C, Price JC, Greer P, Sutton-Tyrrell K, van der Veen FM, and Meltzer CC. Reduced cerebral blood flow response and compensation among patients with untreated hypertension. Neurology 64: 1358 –1365, 2005. 38. Kasischke KA, Vishwasrao HD, Fisher PJ, Zipfel WR, and Webb WW. Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis. Science 305: 99 –103, 2004. 39. Kazama K, Anrather J, Zhou P, Girouard H, Frys K, Milner TA, and Iadecola C. Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals. Circ Res 95: 1019 –1026, 2004. 40. Kazama K, Wang G, Frys K, Anrather J, and Iadecola C. Angiotensin II attenuates functional hyperemia in the mouse somatosensory cortex. Am J Physiol Heart Circ Physiol 285: H1890 –H1899, 2003. J Appl Physiol • VOL
41. Ko KR, Ngai AC, and Winn HR. Role of adenosine in regulation of regional cerebral blood flow in sensory cortex. Am J Physiol Heart Circ Physiol 259: H1703–H1708, 1990. 42. Krainik A, Hund-Georgiadis M, Zysset S, and von Cramon DY. Regional impairment of cerebrovascular reactivity and BOLD signal in adults after stroke. Stroke 36: 1146 –1152, 2005. 43. Krimer LS, Muly EC 3rd, Williams GV, and Goldman-Rakic PS. Dopaminergic regulation of cerebral cortical microcirculation. Nat Neurosci 1: 286 –289, 1998. 44. Krizanac-Bengez L, Mayberg MR, and Janigro D. The cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in vascular homeostatis and pathophysiology. Neurol Res 26: 846 – 853, 2004. 45. Kuschinsky W, Wahl M, Bosse O, and Thurau K. Perivascular potassium and pH as determinants of local pial arterial diameter in cats. A microapplication study. Circ Res 31: 240 –247, 1972. 46. Lassen NA. Cerebral blood flow and oxygen consumption in man. Physiol Rev 39: 183–238, 1959. 47. Li J and Iadecola C. Nitric oxide and adenosine mediate vasodilation during functional activation in cerebellar cortex. Neuropharmacology 33: 1453–1461, 1994. 48. Lindauer U, Megow D, Matsuda H, and 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. 49. Lovick TA, Brown LA, and Key BJ. Neurovascular relationships in hippocampal slices: physiological and anatomical studies of mechanisms underlying flow-metabolism coupling in intraparenchymal microvessels. Neuroscience 92: 47– 60, 1999. 50. Mentis MJ, Horwitz B, Grady CL, Alexander GE, VanMeter JW, Maisog JM, Pietrini P, Schapiro MB, and Rapoport SI. Visual cortical dysfunction in Alzheimer’s disease evaluated with a temporally graded “stress test” during PET. Am J Psychiatry 153: 32– 40, 1996. 51. Montecot C, Seylaz J, and Pinard E. Carbon monoxide regulates cerebral blood flow in epileptic seizures but not in hypercapnia. Neuroreport 9: 2341–2346, 1998. 52. Mulligan SJ and MacVicar BA. Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431: 195–199, 2004. 53. Ngai AC and Winn HR. Pial arteriole dilation during somatosensory stimulation is not mediated by an increase in CSF metabolites. Am J Physiol Heart Circ Physiol 282: H902–H907, 2002. 54. Nguyen TS, Winn HR, and Janigro D. ATP-sensitive potassium channels may participate in the coupling of neuronal activity and cerebrovascular tone. Am J Physiol Heart Circ Physiol 278: H878 –H885, 2000. 55. Niwa K, Araki E, Morham SG, Ross ME, and Iadecola C. Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex. J Neurosci 20: 763–770, 2000. 56. Niwa K, Carlson GA, and Iadecola C. Exogenous A1– 40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice. J Cereb Blood Flow Metab 20: 1659 –1668, 2000. 57. Niwa K, Haensel C, Ross ME, and Iadecola C. Cyclooxygenase-1 participates in selected vasodilator responses of the cerebral circulation. Circ Res 88: 600 – 608, 2001. 58. Niwa K, Kazama K, Younkin L, Younkin SG, Carlson GA, and Iadecola C. Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein. Am J Physiol Heart Circ Physiol 283: H315–H323, 2002. 59. Niwa K, Porter VA, Kazama K, Cornfield D, Carlson GA, and Iadecola C. A-peptides enhance vasoconstriction in cerebral circulation. Am J Physiol Heart Circ Physiol 281: H2417–H2424, 2001. 60. Niwa K, Younkin L, Ebeling C, Turner SK, Westaway D, Younkin S, Ashe KH, Carlson GA, and Iadecola C. A1– 40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proc Natl Acad Sci USA 97: 9735–9740, 2000. 61. Northington FJ, Matherne GP, and Berne RM. Competitive inhibition of nitric oxide synthase prevents the cortical hyperemia associated with peripheral nerve stimulation. Proc Natl Acad Sci USA 89: 6649 – 6652, 1992. 62. Norup Nielsen A and Lauritzen M. Coupling and uncoupling of activitydependent increases of neuronal activity and blood flow in rat somatosensory cortex. J Physiol 533: 773–785, 2001. 63. Park L, Anrather J, Forster C, Kazama K, Carlson GA, and Iadecola C. Abeta-induced vascular oxidative stress and attenuation of functional hyperemia in mouse somatosensory cortex. J Cereb Blood Flow Metab 24: 334 –342, 2004.
100 • JANUARY 2006 •
www.jap.org
Invited Review NEUROVASCULAR COUPLING 64. Park L, Anrather J, Zhou P, Frys K, Pitstick R, Younkin S, Carlson GA, and Iadecola C. NADPH oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid beta peptide. J Neurosci 25: 1769 –1777, 2005. 65. Paulson OB and Newman EA. Does the release of potassium from astrocyte endfeet regulate cerebral blood flow? Science 237: 896 – 898, 1987. 66. Pellerin L, Pellegri G, Bittar PG, Charnay Y, Bouras C, Martin JL, Stella N, and Magistretti PJ. Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle. Dev Neurosci 20: 291–299, 1998. 67. Peng X, Carhuapoma JR, Bhardwaj A, Alkayed NJ, Falck JR, Harder DR, Traystman RJ, and Koehler RC. Suppression of cortical functional hyperemia to vibrissal stimulation in the rat by epoxygenase inhibitors. Am J Physiol Heart Circ Physiol 283: H2029 –H2037, 2002. 68. Peters APS and Webster HD. The Fine Structure of the Nervous System. New York: Oxford University Press, 1991. 69. Pineiro R, Pendlebury S, Johansen-Berg H, and Matthews PM. Altered hemodynamic responses in patients after subcortical stroke measured by functional MRI. Stroke 33: 103–109, 2002. 70. Rother J, Knab R, Hamzei F, Fiehler J, Reichenbach JR, Buchel C, and Weiller C. Negative dip in BOLD fMRI is caused by blood flow— oxygen consumption uncoupling in humans. Neuroimage 15: 98 –102, 2002. 71. Roy C and Sherrington C. On the regulation of the blood-supply of the brain. J Physiol 11: 85–108, 1890. 72. Rubio R, Berne RM, Bockman EL, and Curnish RR. Relationship between adenosine concentration and oxygen supply in rat brain. Am J Physiol 228: 1896 –1902, 1975. 73. Schmidt C. The Cerebral Circulation in Health and Disease. Springfield, IL: Thomas, 1950. 74. Scremin OU, Rovere AA, Raynald AC, and Giardini A. Cholinergic control of blood flow in the cerebral cortex of the rat. Stroke 4: 232–239, 1973. 75. Segal SS. Regulation of blood flow in the microcirculation. Microcirculation 12: 33– 45, 2005. 76. Selkoe DJ and Schenk D. Alzheimer’s disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol 43: 545–584, 2003. 77. Smith CD, Andersen AH, Kryscio RJ, Schmitt FA, Kindy MS, Blonder LX, and Avison MJ. Altered brain activation in cognitively intact individuals at high risk for Alzheimer’s disease. Neurology 53: 1391–1396, 1999.
J Appl Physiol • VOL
335
78. Traystman RJ, Kirsch JR, and Koehler RC. Oxygen radical mechanisms of brain injury following ischemia and reperfusion. J Appl Physiol 71: 1185–1195, 1991. 79. Walder CE, Green SP, Darbonne WC, Mathias J, Rae J, Dinauer MC, Curnutte JT, and Thomas GR. Ischemic stroke injury is reduced in mice lacking a functional NADPH oxidase. Stroke 28: 2252–2258, 1997. 80. Wang H, Hitron IM, Iadecola C, and Pickel VM. Synaptic and vascular associations of neurons containing cyclooxygenase-2 and nitric oxide synthase in rat somatosensory cortex. Cereb Cortex 15: 1250 –1260, 2005. 81. Ward NL and Lamanna JC. The neurovascular unit and its growth factors: coordinated response in the vascular and nervous systems. Neurol Res 26: 870 – 883, 2004. 82. Warkentin S and Passant U. Functional imaging of the frontal lobes in organic dementia. Regional cerebral blood flow findings in normals, in patients with frontotemporal dementia and in patients with Alzheimer’s disease, performing a word fluency test. Dement Geriatr Cogn Disord 8: 105–109, 1997. 83. Yaksh TL, Wang JY, and Go VL. Cortical vasodilatation produced by vasoactive intestinal polypeptide (VIP) and by physiological stimuli in the cat. J Cereb Blood Flow Metab 7: 315–326, 1987. 84. Yang G, Huard JM, Beitz AJ, Ross ME, and Iadecola C. Stellate neurons mediate functional hyperemia in the cerebellar molecular layer. J Neurosci 20: 6968 – 6973, 2000. 85. Yang G and Iadecola C. Glutamate microinjections in cerebellar cortex reproduce cerebral vascular effects of parallel fiber stimulation. Am J Physiol Regul Integr Comp Physiol 271: R1568 –R1575, 1996. 86. Yang G and Iadecola C. Obligatory role of NO in glutamate-dependent hyperemia evoked from cerebellar parallel fibers. Am J Physiol Regul Integr Comp Physiol 272: R1155–R1161, 1997. 87. Yang G, Zhang Y, Ross ME, and Iadecola C. Attenuation of activityinduced increases in cerebellar blood flow in mice lacking neuronal nitric oxide synthase. Am J Physiol Heart Circ Physiol 285: H298 –H304, 2003. 88. Zhang F, Eckman C, Younkin S, Hsiao KK, and Iadecola C. Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein. J Neurosci 17: 7655–7661, 1997. 89. Zlokovic BV, Deane R, Sallstrom J, Chow N, and Miano JM. Neurovascular pathways and Alzheimer amyloid beta-peptide. Brain Pathol 15: 78 – 83, 2005. 90. Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, and Carmignoto G. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6: 43–50, 2003.
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