Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease

Abstract

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.

Full text

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 de-
pendent 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, endothe-
lial 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 hyperten-
sion, Alzheimer disease, and ischemic stroke. Consequently, CBF is no longer
matched to the metabolic requirements of the tissue. This cerebrovascular dysregu-
lation 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 homeo-
static unbalance may contribute to brain dysfunction. This
review provides a brief summary of neurovascular coupling in
the normal state and in diseases including hypertension, ische-
mic 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 (astro-
cytes, microglia, oligodendrocytes), and vascular cells (endo-
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 neu-
rovascular 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 sep-
arated from the brain by the Virchow-Robin space, which
contains cerebrospinal fluid. On the outer side of the Virchow-
Robin space, astrocytes give rise to the glia limitans mem-
brane. As the arterioles penetrate deeper into the brain, the
Virchow-Robin space disappears and the vascular basement
Address for reprint requests and other correspondence: C. Iadecola, Division
of Neurobiology, 411 East 69th St., Rm. KB410, New York, NY 10021
(e-mail: coi2001@med.cornell.edu).
J Appl Physiol 100: 328 –335, 2006;
doi:10.1152/japplphysiol.00966.2005.
8750-7587/06 $8.00 Copyright
©
2006 the American Physiological Society http://www. jap.org328

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 astro-
cytic 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. Endo-
thelial 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 hyper-
polarizing factor, and endothelin (19). Pericytes have contrac-
tile properties and may modulate capillary diameter (31).
Perivascular astrocytes surround most of the capillary ablumi-
nal 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).
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 neuro-
vascular coupling (Table 1). These include ions, metabolic
by-products, vasoactive neurotransmitters, and vasoactive fac-
tors released in response to neurotransmitters.
Vasoactive ions. K
⫹
and H
⫹
are generated by the extracel
-
lular 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
muscle cells (20, 54), leading to their hyperpolarization and
subsequent relaxation. During sustained activation, ATP de-
pletion could lead to opening of ATP-sensitive K
⫹
channels
(K
ATP
) on vessels. Therefore, K
ATP
channels have been impli
-
cated in the mechanisms of neurovascular coupling (54). Fur-
thermore, K
ATP
could also participate in neurovascular cou
-
pling 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 Ca
2⫹
may produce vasodilation (28).
Vasoactive factors related to energy metabolism. The brain
has little energy reserve and requires a continuous supply of
glucose and O
2
through CBF. A sudden increase in the demand
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.
Table 1. Factors implicated in neurovascular coupling
Agent References
Vasoactive ions
K
⫹
45
H
⫹
45
Ca
2⫹
28
Metabolic factors
Lactate, CO
2
71, 73
Hypoxia 73
Adenosine 72
Vasoactive neurotransmitters
Dopamine 43
GABA 22
Acetylcholine 74
Vasoactive intestinal peptide 83
Other
NO 61
COX-2 products 55
P450 products 67
CO 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 O
2
and glucose, which may be a factor in triggering the
hemodynamic response (3). However, the reduction in brain O
2
concentration at the site of activation is small and transient and
cannot account for sustained increases in flow (2). Further-
more, the CBF response to activation is not altered by hypo-
glycemia or hypoxia, suggesting that lack of glucose or O
2
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 cerebel-
lum (47) and cerebral cortex (41). Lactate produced during
brain activation could also be an important mediator of func-
tional hyperemia by increasing H
⫹
concentration and produc
-
ing 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 hippocam-
pal 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 O
2
(“dip”) observed at the onset of
activation with optical imaging, functional MRI, and O
2
elec
-
trodes (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 neurotrans-
mitters. It has long been proposed that vasoactive neurotrans-
mitters released during neural activity contribute to the vaso-
dilation (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 acti-
vation 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. Vaso-
active factors can also be generated by the intracellular signal-
ing induced by activation of neurotransmitter receptors. For
example, activation of glutamate receptors produces vaso-
dilation and increases blood flow. In neocortex and hip-
pocampus, 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-methylisoxazole-
propionic acid (CAMPA) and/or NMDA receptor blockers (1,
33, 62). Because glutamate is not vasoactive in isolated cere-
bral arteries (18), the vasodilation is mediated by vasoactive
factors whose synthesis is triggered by the changes in intracel-
lular Ca
2⫹
associated with glutamate receptor activation. The
increase in Ca
2⫹
activates Ca
2⫹
-dependent enzymes that pro
-
duce potent vasodilators. One such enzyme is the neuronal
isoform of NO synthase (nNOS), which produces the vasodi-
lator 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 inhib-
itors (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 ob-
served also in nNOS null mice (86, 87). These findings suggest
that, in cerebellum, NO plays an obligatory role in the mech-
anisms of the vasodilation.
The increase in intracellular Ca
2⫹
evoked by glutamate also
activates phospholipase A2, leading to production of arachi-
donic acid. Arachidonic acid is then metabolized by the cyclo-
oxygenase (COX) pathway, producing vasodilatatory prosta-
glandins (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 metabo-
lites 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 in-
crease in CBF produced by activation (see Koehler RC, Ge-
bremedhin 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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330 NEUROVASCULAR COUPLING
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astrocytes, leading to increases in intracellular Ca
2⫹
, COX
activation, and local vasodilation (90). A critical role for Ca
2⫹
fluxes from neurons to astrocytes and arterioles is also sup-
ported by another study in brain slices (23). Arterioles at rest
exhibit periodic contractions and relaxations, called vasomo-
tion, a phenomenon resulting from Ca
2⫹
oscillations in smooth
muscle cells (23). It was found that electrical stimulation of
brain slices induces Ca
2⫹
waves in astrocytes, which then
propagate to arterioles and inhibit vasomotion (23). The inhi-
bition 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 Ca
2⫹
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 be-
cause they provide evidence that activity-induced Ca
2⫹
tran
-
sients 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 opti-
mize 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 vasodi-
lation of Duling and Berne (75). Indeed, retrograde vasodila-
tion in response to ATP has been observed in isolated rat
cerebral arterioles (12), whereas upstream vasodilation has
been demonstrated in cerebellar cortex arterioles during acti-
vation 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 re-
sponse 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 up-
stream 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 vasodi-
lator substances from the glia limitans adjacent to upstream
pial arteries plays a role in remote vasodilation because flush-
ing 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 prop-
agation 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, peri-
cytes, 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 hyper-
tension, 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 struc-
tural alterations facilitate vascular occlusions and compromise
cerebral perfusion. In addition, hypertension impairs the func-
tion of cerebral blood vessels (17, 27). Hypertension impairs
endothelium-dependent relaxation (19) and alters cerebrovas-
cular 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 somato-
sensory 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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does not reproduce the effects of ANG II on functional hyper-
emia. Although these observations suggest that the cerebrovas-
cular effect of short-term administration of ANG II is indepen-
dent 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 (Ta-
ble 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 indi-
viduals (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 coex-
isting 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 de-
mentia and is characterized by deposition of amyloid ␤-peptide
(A␤) in the neuropil (neuritic plaques) and blood vessels
(amyloid angiopathy), and by accumulation of hyperphospho-
rylated 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 dys-
function 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, re-
sponses to vasoconstrictors are exaggerated (35, 59). Func-
tional hyperemia is impaired and cerebrovascular autoregula-
tion 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
A␤
1– 40
on the neocortex (56, 63). Furthermore, alterations in
vascular reactivity can also be observed in isolated vessels of
normal mice exposed to A␤
1– 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 exacer-
bate the dementia (31). Furthermore, insufficient CBF may
alter A␤ trafficking across the blood-brain barrier (89). There-
fore, 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 de-
mentia.
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 hypoper-
fusion). After ischemia, the cerebral circulation is in a state of
vasoparalysis (30). After ischemic stroke in patients, the reac-
Table 2. Alterations in functional hyperemia in Alzheimer disease, cerebrovascular diseases,
and hypertension: selected human studies
Pathology Activation Task
Method for CBF
Detection Effect on Cortical Hemodynamic Change Reference
Alzheimer disease and APOE␧ genotype
Alzheimer disease Visual stimulus PET 2 Middle temporal 50
Alzheimer disease Verbal task PET and NIRS 2 Parietal, frontal 29
Alzheimer disease Verbal task Xenon-133 2 Dorsolateral 82
APOEε4 carriers Visual naming and letter task fMRI 2 Prefrontal 77
APOEε4 carriers Memory tasks fMRI 2 Mid and posterior inferior temporal 4
Cerebrovascular diseases
Ischemic stroke with full recovery Hand grip fMRI 2 Left hippocampus 42
Lacunar stroke Finger tapping fMRI 2 Somatosensory cortex, supplementary
motor area
69
Extra- and intracranial stenosis Hand grip fMRI 2 Somatosensory cortex, supplementary
motor area
26
Common carotid or vertebral
artery occlusion
Finger tapping fMRI 2 Supplementary motor area 70
Internal carotid or middle cerebral
artery occlusion
Bimanual motor tasks PET No change in somatosensory cortex 36
Essential hypertension Memory task PET 2 Posterior parietal 37
CBF, cerebral blood flow; PET, positron emission tomography; NIRS: near-infrared spectroscopy; fMRI, functional magnetic resonance imaging; 2,
attenuation of the CBF increase.
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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 reduc-
tion 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.
Vascular Oxidative Stress: a Final Common Pathway to
Cerebrovascular Dysfunction
There is accumulating evidence that vascular oxidative
stress leads to profound alterations in cerebrovascular regula-
tion (16). Hypertension, AD, and cerebral ischemia are asso-
ciated 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 ob-
served 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 scav-
enging 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 ob-
served in hypertension and AD. Indeed, ROS scavengers
ameliorate the disturbance in CBF produced by ischemia-
reperfusion (30, 78), but it is not known whether ROS scav-
engers 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 hyperten-
sion and AD, whereas mice lacking the catalytic subunit of the
enzyme (gp91
phox
) are protected from the deleterious cerebro
-
vascular effects of hypertension or A␤ (39, 64). Mice lacking
gp91
phox
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 eluci-
dated in sufficient detail. New and powerful tools are needed to
probe into the functional relationship among these cells with-
out 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 dysregula-
tion contribute to the overall brain dysfunction. Vascular dys-
regulation may prove to be a valuable therapeutic target in a
wide variety of brain diseases.
ACKNOWLEDGMENTS
We thank Dr. Carrie Drake for comments.
GRANTS
This research was supported by National Institutes of Health Grants
HL-18974 and NS-37853.
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