Hypoxic regulation of the fetal cerebral circulation

William Pearce
J Appl Physiol 100:731-738, 2006. doi:10.1152/japplphysiol.00990.2005

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J Appl Physiol 100: 731–738, 2006;
doi:10.1152/japplphysiol.00990.2005. Invited Review

HIGHLIGHTED TOPIC Regulation of the Cerebral Circulation

Hypoxic regulation of the fetal cerebral circulation

William Pearce
Departments of Physiology, Pharmacology, and Biochemistry, Center for Perinatal
Biology, Loma Linda University School of Medicine, Loma Linda, California

Pearce, William. Hypoxic regulation of the fetal cerebral circulation. J Appl

Physiol 100: 731–738, 2006; doi:10.1152/japplphysiol.00990.2005.—Fetal cere-
brovascular responses to acute hypoxia are fundamentally different from those
observed in the adult cerebral circulation. The magnitude of hypoxic vasodilatation
in the fetal brain increases with postnatal age although fetal cerebrovascular
responses to acute hypoxia can be complicated by age-dependent depressions of
blood pressure and ventilation. Acute hypoxia promotes adenosine release, which
depresses fetal cerebral oxygen consumption through action of adenosine on
neuronal A1 receptors and vasodilatation through activation of A2 receptors on
cerebral arteries. The vascular effect of adenosine can account for approximately

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half the vasodilatation observed in response to hypoxia. Hypoxia-induced release of
nitric oxide and opioids can account for much of the adenosine-independent
cerebral vasodilatation observed in response to hypoxia in the fetus. Direct effects
of hypoxia on cerebral arteries account for the remaining fraction, although the
vascular endothelium contributes relatively little to hypoxic vasodilatation in the
immature cerebral circulation. In contrast to acute hypoxia, fetal cerebral blood
flow tends to normalize during acclimatization to chronic hypoxia even though
cardiac output is depressed. However, uncompensated chronic hypoxia in the fetus
can produce significant changes in brain structure and function, alteration of
respiratory drive and fluid balance, and increased incidence of intracranial hemor-
rhage and periventricular leukomalacia. At the level of the fetal cerebral arteries,
chronic hypoxia increases protein content and depresses norepinephrine release,
contractility, and receptor densities associated with contraction but also attenuates
endothelial vasodilator capacity and decreases the ability of ATP-sensitive and
calcium-sensitive potassium channels to promote vasorelaxation. Overall, fetal
cerebrovascular adaptations to chronic hypoxia appear prioritized to conserve
energy while preserving basic contractility. Many gaps remain in our understanding
of how the effects of acute and chronic hypoxia are mediated in fetal cerebral
arteries, but studies of adult cerebral arteries have produced many powerful
pharmacological and molecular tools that are simply awaiting application in studies
of fetal cerebral artery responses to hypoxia.
cerebral arteries; neonate; high altitude; perivascular innervation; vascular endo-
thelium

ONE OF THE MOST FUNDAMENTAL principles of cardiovascular
regulation is that it should efficiently match each tissue’s blood
flow with its metabolic demands. This principle applies not
only to fully mature adult tissues but also to the immature
tissues of the fetus in which oxygen consumption is typically
high despite a low arterial PO2 (85). An important feature of
this regulation in the fetus is that at the lower limits of oxygen
availability, blood flow is centralized to favor the brain and
heart at the expense of other organs and tissues (104). In
extreme situations in which this regulation succumbs to over-
whelming peripheral vasodilatation, hypotension ensues with
resultant hypoxic-ischemic cerebral damage (52). Such dam-
age is rarely fully reversible and often yields lifelong neuro-
Address for reprint requests and other correspondence: W. J. Pearce, Center
for Perinatal Biology, Loma Linda Univ. School of Medicine, Loma Linda, CA
92350 (e-mail: wpearce@llu.edu).
http://www. jap.org 8750-7587/06 $8.00 Copyright © 2006 the American Physiological Society
logical morbidity that is graded with the severity and duration
of the insult (48, 76, 102). Fortunately, long before these
extremes are reached, the fetus can elicit a broad variety of
vascular responses that help maintain cerebral homeostasis
during low-oxygen conditions. Among these are the special-
ized mechanisms that mediate the short-term vasodilatory re-
sponses to acute hypoxia and the more long-term changes in
artery structure and reactivity that enable the fetus to adapt to
chronic hypoxia. The purpose of this review is to summarize
the main features of these fetal cerebrovascular adjustments,
with separate emphasis on responses to acute and chronic
hypoxia.
KEY CHARACTERISTICS OF FETAL CEREBROVASCULAR
RESPONSES TO ACUTE HYPOXIA
Owing in large part to its rapid pace of growth and synthesis,
the fetal brain exhibits greater rates of cerebral oxygen con-
731
Invited Review
732 HYPOXIA AND THE FETAL CEREBRAL CIRCULATION
sumption than measured in the adult brain. This active metab-
olism is closely coupled to oxygen delivery (61), even during
periods of mild cerebral hypothermia (27). This coupling also
includes a strong influence of oxygen delivery on oxygen
consumption, because acute hypoxia elicits significant de-
creases in neuronal activity and cerebral metabolic rate (78)
even though cellular oxygenation is not low enough to directly
limit metabolism (39). This ability of hypoxia to inhibit cere-
bral metabolic rate appears to be the primary mechanism used
by the llama fetus, which is extraordinarily well adapted to
altitude hypoxia, when faced with an acute hypoxic challenge
(69). In most fetal mammals, however, the response to acute
hypoxia includes both an increase in blood flow to maintain
oxygen delivery and an inhibition of oxidative metabolism (78).
The ability to increase cerebral perfusion in response to
acute hypoxia appears early in fetal development and has been
demonstrated at less than 0.7 gestation (65), although there is
some doubt that at this age the extent of vasodilatation is able
to totally compensate for decreased arterial oxygen content
(42). Similarly, the use of Doppler techniques has enabled
demonstration of hypoxic cerebral vasodilation in premature
human infants (34) as well as in fetal lambs, in utero (66).
Across all of these responses to acute hypoxia, one consistent
feature is that the magnitude of the response is age dependent
and peaks in the early postnatal period (15).
Another important feature of hypoxic vasodilatation in the
fetal brain is that it is highly heterogeneous both among
different brain regions and among adjacent tissue compart-
ments (17, 60). As shown in studies of adult brain, hypoxic
vasodilatation in the fetal brain is most robust in the brain stem
(26). The fetal brain stem is also more resistant to hypoxic
damage than other brain areas and initiates a robust neovascu-
larization in response to hypoxia (118). One consequence of
the strong brain stem vasodilator response to acute hypoxia is
that the increased flow can depress CO2 in the cisterna and
thereby transiently depress ventilation (33, 45). This effect also
appears to be age dependent and becomes more pronounced as
sensitivity to CO2 increases with postnatal age (15). In multiple
species, acute hypoxia can also precipitate hypotension, and,
again, the magnitude of this response is age dependent with the
greatest effect in the early postnatal period (15, 103, 133). This
effect appears to be mediated in part by chemoreceptor-medi-
ated bradycardia, but aside from this influence there appears to
be little participation of the carotid chemoreflexes in fetal
responses to acute hypoxia (51, 60), although these reflexes are
fully developed in the adult (56).
TISSUE MEDIATORS OF ACUTE HYPOXIC CEREBRAL
VASODILATATION IN THE FETUS
Coupling between blood flow and metabolism depends
heavily on a negative feedback loop between tissue production
of vasodilator metabolites and the level of contractile tone in
the arteries and arterioles supplying the tissue. In this context,
one of most important molecules signaling an increase in
metabolic demand relative to oxygen delivery is adenosine. As
shown in a broad variety of studies, tissue adenosine release
mediates a significant fraction of the cerebral vasodilatation
produced by hypoxia (94) through action on adenosine A2
receptors (18), and this response is fully developed by 0.6
gestation in most species (65). In addition, release of cerebral
J Appl Physiol • VOL 100 • FEBRUARY 2006 •
adenosine also helps mediate hypoxic inhibition of fetal breath-
ing movements (62) and neonatal ventilation (116). Interest-
ingly, adenosine also appears to mediate hypoxic depression of
fetal cerebral metabolism through action on adenosine A1
receptors (19). Clearly, in the fetus as in the adult (95),
adenosine is a critically important mediator of cerebrovascular
homeostasis during acute hypoxic insults, as summarized in
Fig. 1.
Despite adenosine’s importance in hypoxic cerebral vasodi-
latation, it is not the only mediator of this response. Pharma-
cological antagonism of adenosine A2 receptors inhibits only
about half the increase in fetal cerebral blood flow produced by
acute hypoxia (19), indicating a role for other mechanisms.
Although hypoxia can increase cerebral PGE2 levels, it has no
significant effect on prostacyclin or thromboxane release (84),
suggesting that prostanoids play at best a modest role in
hypoxic cerebral vasodilatation in the immature brain (67).
Other possible mediators include vasopressin, but the role of
this molecule appears to be highly dependent on both brain
region and species (47, 107). Hypoxia may also increase
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cerebrospinal fluid levels of pituitary adenylate cyclase-acti-
vating peptide that, in turn, have been associated with release
of vasodilator opioids (126). Other evidence suggests that
hypoxia may promote release of opioids such as methionine
enkephalin linked to production of nitric oxide and cGMP (5,
125). Regardless of whether the source of this nitric oxide is
from neurons (126) or the vascular endothelium, the accumu-
lated evidence suggests important interactions between nitric
oxide, cGMP, and opioid release during acute hypoxia in the
immature brain (7) (see Fig. 1). How opioids contribute to
hypoxic cerebral vasodilatation in the adult brain, however, has
not been well studied and remains controversial.
DIRECT VASCULAR EFFECTS OF ACUTE HYPOXIA IN FETAL
CEREBRAL ARTERIES
The brain parenchyma includes many different cell types,
and each of these can release a different combination of
vasoactive factors in response to hypoxia. In addition to the
vasodilator molecules mentioned above, hypoxia can also stim-
ulate some fetal cells to release contractile neurotransmitters
such as serotonin and other monoamines (16, 54). The net
result is that hypoxia initiates a dramatic and regionally heter-
ogeneous change in the interstitial milieu that may not only
promote vasodilatation but may also attenuate vasodilatation to
some receptor agonists, such as N-methyl-D-aspartate (8). The
reasons for this complexity arise not only from the mixtures of
cerebral cell types that vary from region to region but also from
the arteries and arterioles whose reactivity is labile and varies
with age, artery size, and region.
One of the most important causes of hypoxia-induced
changes in vasoreactivity is the direct effect of hypoxia on
endothelial function. Endothelial vasodilator capacity is
typically depressed in fetal cerebral arteries (99), and the
endothelium contributes relatively little to hypoxic vasodi-
latation in the fetus (132). This may be due in part to the fact
that oxygen is a key reactant in the synthesis of nitric oxide
but is of limited availability in the fetus, where oxygen
tensions well below 40 Torr are normal (55, 124). However,
postnatal maturation imparts an increasing capacity for both
pharmacologically induced and shear-induced endothelium-
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 Invited Review
HYPOXIA AND THE FETAL CEREBRAL CIRCULATION 733

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Fig. 1. Summary of combined effects of acute hypoxia, chronic hypoxia, and maturation on cerebrovascular tone. This diagram summarizes the main effects of
acute and chronic hypoxia discussed in the accompanying text. For reference, corresponding effects of postnatal maturation are also shown. The effects of each
influence are indicated by the enclosed abbreviations defined at the top of the figure (A-, A⫹, C-, C⫹, M-, and M⫹). Circled ⫹ signs indicate stimulation of
a pathway, and conversely, circled ⫺ signs indicate inhibition. This diagram is not intended to be comprehensive but rather is given as an overview of known
sites of action of hypoxia on the pathways governing cerebrovascular tone. sGC, soluble guanylate cyclase; cGMP, cyclic guanosine monophosphate; PKG, cyclic
guanosine monophosphate-activated protein kinase; PG(EP), prostaglandin/E-prostanoid; BK, large conductance calcium-sensitive potassium channel; KATP,
ATP-sensitive potassium channel; eNOS, endothelial nitric oxide synthetase; COX, cyclooxygenase; NE, norepinephrine; NO, nitric oxide.

dependent vasodilatation (123), and, correspondingly, the
endothelial contribution to hypoxic vasodilatation increases
throughout early postnatal life and becomes quite prominent
in adult cerebral arteries (97, 132). Although there is some
evidence that endothelial release of prostanoids may medi-
ate some of the endothelium’s contribution to hypoxic
vasodilatation (83), other more extensive evidence attributes
the main endothelial contribution of hypoxic vasodilation to
endothelial release of nitric oxide (31, 50). This interpreta-
tion is not universal (46), but it suggests that hypoxia-
induced release of nitric oxide from the endothelium and
subsequent cGMP formation are an important, if variable
and age-dependent, component of the fetal cerebral response
to acute hypoxia (31, 50) (see Fig. 1).
Apart from the endothelium, hypoxia also exerts multiple
direct effects on vascular smooth muscle (95). Immature cere-
bral arteries produce less active stress than adult arteries and
are less resistant to the direct effects of acute hypoxia (96). An
important consequence of these vascular characteristics is that
the smaller and more peripheral cerebral arteries relax quickly
and completely in response to hypoxia, whereas the larger and
J Appl Physiol • VOL
more proximal arteries, including the common carotid, main-
tain tone much better and play a more important role in the
gradual adjustments of cerebrovascular resistance to hypoxia
(40, 96). At the level of the smooth muscle, acute hypoxia can
alter membrane potential and calcium influx in fetal smooth
muscle (30) (see Fig. 1), although these responses have not
been directly determined in fetal cerebral arteries. Hypoxia can
also depress the density and binding affinity of G protein-
coupled receptors for contractile agonists (3) but does not
appear to directly influence the coupling of these receptors to
inositol trisphosphate formation in fetal carotid arteries (2).
Acute hypoxia also has been reported to activate calcium-
sensitive potassium channels in neonatal pial arteries through a
nitric oxide-independent mechanism (6). Within the adventitia
of the artery wall, acute hypoxia may also promote the release
of vasodilator sensory neuropeptides (49) but may also inhibit
release of nitric oxide (91) from perivascular nerves in adult
cerebral arteries. Without doubt, acute hypoxia exerts multiple
direct effects on arteries, in vitro, but many of these effects
await examination in arteries isolated from the fetal cerebral
circulation.
100 • FEBRUARY 2006 • www.jap.org
Invited Review
734 HYPOXIA AND THE FETAL CEREBRAL CIRCULATION

EFFECTS OF CHRONIC HYPOXIA ON THE FETAL BRAIN with robust increases in capillary density in response to hyp-
oxia (112). Both vascular endothelial growth factor and eryth-
Chronic hypoxia produces a pattern of responses very dif-
ropoietin are important components of the endocrine response
ferent from those elicited by acute hypoxia. With sustained
to chronic hypoxia, and in turn these bring about multiple
hypoxia, plasma hemoglobin concentrations rise and blood
changes of significance for cardiovascular and cerebrovascular
flows to most fetal organs tend to normalize but with sustained
regulation (81). Chronic hypoxia increases protein content in
reductions in oxygen delivery to most organs other than the
fetal cerebral arteries, depresses the magnitude of depolariza-
brain and heart (14). Fetal cardiac output is typically depressed
tion-induced contractions, and also depresses the densities of
by moderate chronic hypoxia, but cerebral blood flow is
several receptor types that drive contraction in these arteries
maintained, as is the vasodilatory response to acute hypoxia
(71, 120). In turn, inositol trisphosphate mobilization and
(55). Much of this compensation for chronic hypoxia appears
receptor density are also depressed by chronic hypoxia (131).
to be facilitated by the maternal circulation (20). In contrast,
At the same time, in distal branches of fetal middle cerebral
maternal pathologies such as placental insufficiency (90) and
arteries, hypoxia enhances the affinity of 5-HT receptors for
hypertension (35) can cause chronic fetal hypoxia, in which
serotonin in the neonate (114). Also in fetal middle cerebral
cases the fetal compensations for chronic hypoxia can be quite
arteries, chronic hypoxia appears to attenuate the ability of
heterogeneous. Chronic fetal hypoxia has been associated with
ATP-sensitive and calcium-sensitive potassium channels to
low birth weights (92, 121) and a variety of changes in brain
promote relaxation (70). In ovine cerebral arteries, chronic
structure, neuronal density, and function (88, 90, 105) as well
hypoxia downregulates the ability of calcium to promote my-
as a broad range of cerebral pathologies, including increased
osin phosphorylation, but this effect is more than offset by an
incidence of intracranial hemorrhage (130) and periventricular
upregulated ability of phosphorylated myosin to produce force

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leukomalacia (113). Acclimatization to chronic hypoxia during
(see Fig. 1). The net effect of these changes is to yield
fetal life has also been suggested to have an adverse influence
increased myofilament calcium sensitivity in fetal cerebral
on adult cardiovascular health (9).
arteries (89). This upregulated calcium sensitivity may help to
Given the range and diversity of clinically relevant fetal
preserve the ability of the arteries to contract but with smaller,
responses to chronic hypoxia, a broad variety of studies have
and possibly more energetically efficient, changes in cytosolic
focused on how fetal cerebral tissues alter their characteristics
calcium. However, the combination of depressed overall con-
in response to chronic hypoxia. Thus chronic hypoxia has been
tractility together with decreased potassium channel reactivity
shown to upregulate pontine adenosine receptors (63), suggest-
indicates that the hypoxic fetus is more delicately balanced
ing modulation of hypoxia’s ability to inhibit cerebral metab-
between contraction and relaxation than in the normoxic state.
olism. Chronic hypoxia has also been shown to stimulate
Taken together, these adaptations to chronic hypoxia appear
hypothalamic production of vasopressin and oxytocin (57) and
prioritized to conserve energy while preserving basic contrac-
release of atrial and brain natriuretic peptides (59), indicating
tility. This untested hypothesis seems a reasonable focus for
important potential changes in fetal fluid balance during
future investigations of the molecular mechanisms whereby
chronic hypoxia. Other studies have revealed that expression of
hypoxia is sensed and initiates changes in gene transcription
the enzyme ornithine decarboxylase increases upon exposure
and protein expression leading to hypoxic cerebrovascular
to hypoxia with a time to peak response of ⬃4 h (72, 93).
adaptation. Equally important, it is clear that cerebral arteries
Owing to the key role of ornithine decarboxylase in polyamine
respond very differently to chronic hypoxia in adult and fetal
synthesis related to growth and differentiation, these studies
brain, and the mechanistic basis for these marked differences
indicate a fundamental response at the cellular level that may
remains largely unexplored.
help individual cerebral cells adapt to the demands of chronic
In many cerebral arteries, the interface between the adven-
hypoxia. Other studies have revealed that chronic hypoxia
titial and medial layers is supplied by a broad variety of
stimulates the synthesis of the vasodilator adrenomedullin in
perivascular nerves that exert motor, sensory, and trophic
the fetal cerebral cortex (53), suggesting a mechanism whereby
influences on the smooth muscle and endothelium constituents
the fetal brain may help maintain adequate oxygen delivery
of the artery wall. Not surprisingly, chronic hypoxia changes
under low-oxygen conditions. The vasodilator peptide calcito-
the function of at least some of these nerves. Chronic hypoxia
nin gene-related peptide also appears to play an important role
depresses the function of nitric oxide releasing nerves in the
in fetal adjustments to chronic hypoxia (115), although the
middle cerebral artery, and because these nerves can facilitate
exact role of this peptide in the cerebral circulation remains
norepinephrine release from adrenergic nerves, overall norepi-
largely unexamined. Without doubt, chronic hypoxia brings
nephrine release decreases in chronically hypoxic fetal cerebral
about a diverse sequence of adjustments in neuronal and glial
arteries (22, 23) (see Fig. 1). This response, which is due to a
protein expression and regulation within the fetal brain (see
decrease in the expression of neuronal nitric oxide synthase
Fig. 1). How these changes are coordinated and how they
(nNOS) in the perivascular nitridergic innervation (82), is a
influence overall cerebrovascular regulation remain largely
unique feature of the fetal response to chronic hypoxia and is
unknown.
absent in adult cerebral arteries. Typically, the adrenergic
EFFECTS OF CHRONIC HYPOXIA ON FETAL neurovascular apparatus is less efficient at initiating contrac-
CEREBRAL ARTERIES tion in fetal compared with adult middle cerebral arteries (98),
but chronic hypoxia appears to upregulate the ability of adren-
Aside from hypoxic changes in the cerebral parenchyma, it ergic stimulation to initiate contraction in fetal cerebral arteries
is also clear that chronic hypoxia dramatically alters the com- (41, 73, 74). This effect, combined with the reduced norepi-
position and reactivity of fetal cerebral arteries. The vascula- nephrine release produced by hypoxic acclimatization in fetal
ture of the immature brain is highly plastic and can respond arteries, suggests important changes in synaptic structure
J Appl Physiol • VOL 100 • FEBRUARY 2006 • www.jap.org

HYPOXIA AND THE FETAL CEREBRAL CIRCULATION
and/or function (such as reduced synaptic cleft width or re-
duced reuptake efficiency) that enable a smaller mass of
norepinephrine to yield a stronger contraction, despite postsyn-
aptic downregulation. Again this is a largely untested hypoth-
esis worthy of further examination. In parallel, the effects of
chronic hypoxia on other neurovascular motor systems seem
ripe for exploration, as do the effects of chronic hypoxia on the
important trophic influences these nerves exert on artery phe-
notype and vasoreactivity. In many respects, our understanding
of the effects of chronic hypoxia on the function of the
adrenergic, cholinergic, and peptidergic innervation of fetal
cerebral arteries is still in its infancy and remains an attractive
area for future work.
At the endothelial surface of cerebral arteries, chronic hyp-
oxia also induces several important effects. It has long been
recognized that intrapartum hypoxia disturbs the permeability
of the blood-brain-barrier in human neonates (109). Chronic
hypoxia has also been shown to depress endothelium-depen-
dent vasodilatation in fetal, but not adult, cerebral arteries (71).
This effect is highly conserved across species and has even
been demonstrated in chicken embryos (108). The loss of
endothelial vasodilatory capacity can be attributed to hypoxic
depression of endothelial nitric oxide synthase mRNA and
protein levels in the fetal brain (1) (see Fig. 1) and is thus
similar to the effect of chronic hypoxia on nNOS levels in the
perivascular nerves of fetal cerebral arteries (82). In contrast,
the effects of chronic hypoxia on the expression of nNOS within
the cerebral parenchyma appear to be more variable and species
dependent (38), with some studies reporting an upregulation (1)
and others reporting a downregulation (24, 25). Certainly, nitric
oxide is not the only vasoactive substance released from the
cerebral endothelium, but the effects of chronic hypoxia on these
pathways remain largely unexamined.
FUTURE DIRECTIONS
As is common in fetal physiology, understanding and ap-
preciation of the mechanisms that mediate the cerebrovascular
effects of hypoxia lag far behind what is known in adult
tissues, particularly in relation to the role of hypoxia-inducible
factor (32, 58, 111). Thus many areas need work, and, to attract
the scientific interest necessary to initiate and complete this
work, it may be advantageous first to focus attention on the
clinical causes, consequences, diagnosis, and treatment of
chronic hypoxia in the fetus. As shown in many studies,
humans can adapt successfully to chronic high-altitude hyp-
oxia, but the mechanisms and long-term health consequences
involved are unknown (9, 86). Perhaps more clinically relevant
are the pathological causes of chronic fetal hypoxia, which
include placental insufficiency (28, 79, 101), restricted uterine
blood flow (20), and umbilical cord compression (80). At the
behavioral level, greater attention also needs to be focused on
the connections between maternal drug and alcohol abuse and
fetal hypoxia (43, 129). Although the incidence of intrapartum
fetal asphyxia is only about 2% (77), it would be of great value
to obstetricians and neonatologists if the association between
chronic fetal hypoxia and vulnerability to asphyxic insults were
better defined (106). For neonates with persistent chronic
hypoxia due to pulmonary insufficiency or cyanotic heart
disease (13), there needs to be greater recognition of the fact
that cardiopulmonary bypass and extracorporeal membrane
J Appl Physiol • VOL
Invited Review
735
oxygenation can precipitate multiple long-lasting disturbances
of the cerebral circulation with potentially hypoxic conse-
quences (36, 44).
Regarding the fetal consequences of chronic hypoxia, it has
long been recognized that fetal hypoxemia is strongly associ-
ated with human intrauterine growth retardation (92). This
growth retardation, in turn, may impart a compromised ability
of the cerebral circulation to respond successfully to acute
hypoxia and hypotension (11), although some studies suggest
that in some cases growth retardation may involve a condition-
ing effect that enables the fetus to resist hypoxic cerebral
damage in some species (119). These mechanisms are clearly
worthy of further investigation, as they may provide clues to
improved clinical strategies for management of cerebrovascu-
lar risk in the small-for-gestational-age infant. In parallel, there
is a great abundance of promising opportunities to better
understand how the fetal cerebral circulation responds to both
acute and chronic hypoxia. In this context the three main
categories of mechanisms include the effects of hypoxia on
brain metabolism and production of vasoactive mediators, the
Downloaded from jap.physiology.org on April 12, 2011
direct effects of hypoxia on the smooth muscle and endothe-
lium of cerebral arteries, and how hypoxia influences the
motor, trophic, and sensory functions of the cerebrovascular
perivascular innervation. Within each of these domains, there
is tremendous opportunity for the application of molecular
tools and genetic strains developed for studies of hypoxic adult
arteries to studies of fetal cerebral arteries.
With greater understanding of the mechanisms whereby
hypoxia influences cerebrovascular regulation, new opportuni-
ties should arise through which the subtle effects of fetal
hypoxia could be more readily detected to identify the fetus at
risk. To this end, Doppler methods are becoming increasingly
useful for the detection of chronic hypoxia in utero (4, 10, 110)
provided that the results are interpreted cautiously (64, 117). At
the bedside, another promising tool for diagnosis is near-
infrared spectroscopy, although again the results of such mea-
surements must be interpreted carefully in relation to cerebral
hypoxia (12, 37, 128). A more powerful tool is functional
magnetic resonance imaging, which is impractical for routine
use but offers great ability to assess fetal cerebral oxygenation
and may help identify the at-risk neonate as well as the extent
to which interventions are successful (122). Even more pow-
erful but less practical is magnetic resonance spectroscopy
(MRS), which offers unprecedented opportunities to measure
concentrations of multiple compounds within the cerebral
tissue and how these change in response to hypoxia (29, 75,
128). For example, proton and phosphorus MRS have demon-
strated that hypoxia can dramatically increase the lactate-to-
creatine ratio in cerebral tissue over a time course that corre-
lates tightly with the time course of energy failure (100). Such
measurements have prompted some to conclude that the use of
MRS may revolutionize the detection of fetal cerebral injury
(21). Hopefully, such advances will lead to development of
more efficient therapies that avoid the undesirable cardiovas-
cular and metabolic side effects of many conventional thera-
pies used clinically to manage the posthypoxic fetus (68, 87).
GRANTS
The work reported in this manuscript was supported by National Institutes
of Health Grants HL-54120, HD-31266, and HL-64867 and by the Loma Linda
University School of Medicine.
100 • FEBRUARY 2006 • www.jap.org
Invited Review
736 HYPOXIA AND THE FETAL CEREBRAL CIRCULATION
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