Journal of Applied Physiology Watch the video to learn how APS reaches out to developing nations.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 100: 731-738, 2006; doi:10.1152/japplphysiol.00990.2005
8750-7587/06 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pearce, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pearce, W.

INVITED REVIEW

HIGHLIGHTED TOPICS
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


   ABSTRACT
TOP
 ABSTRACT
KEY CHARACTERISTICS OF FETAL...
 TISSUE MEDIATORS OF ACUTE...
 DIRECT VASCULAR EFFECTS OF...
 EFFECTS OF CHRONIC HYPOXIA...
 EFFECTS OF CHRONIC HYPOXIA...
 FUTURE DIRECTIONS
 GRANTS
 REFERENCES
 
Fetal cerebrovascular 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 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 hemorrhage 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 endothelium

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 overwhelming peripheral vasodilatation, hypotension ensues with resultant hypoxic-ischemic cerebral damage (52). Such damage is rarely fully reversible and often yields lifelong neurological 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 specialized mechanisms that mediate the short-term vasodilatory responses 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
TOP
 ABSTRACT
 KEY CHARACTERISTICS OF FETAL...
TISSUE MEDIATORS OF ACUTE...
 DIRECT VASCULAR EFFECTS OF...
 EFFECTS OF CHRONIC HYPOXIA...
 EFFECTS OF CHRONIC HYPOXIA...
 FUTURE DIRECTIONS
 GRANTS
 REFERENCES
 
Owing in large part to its rapid pace of growth and synthesis, the fetal brain exhibits greater rates of cerebral oxygen consumption than measured in the adult brain. This active metabolism 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 decreases 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 cerebral 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 compartments (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 neovascularization 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-mediated 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
TOP
 ABSTRACT
 KEY CHARACTERISTICS OF FETAL...
 TISSUE MEDIATORS OF ACUTE...
DIRECT VASCULAR EFFECTS OF...
 EFFECTS OF CHRONIC HYPOXIA...
 EFFECTS OF CHRONIC HYPOXIA...
 FUTURE DIRECTIONS
 GRANTS
 REFERENCES
 
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 adenosine also helps mediate hypoxic inhibition of fetal breathing movements (62) and neonatal ventilation (116). Interestingly, 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.


Figure 1
View larger version (36K):
[in this window]
[in a new window]
  		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.

 
Despite adenosine’s importance in hypoxic cerebral vasodilatation, it is not the only mediator of this response. Pharmacological 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 cerebrospinal fluid levels of pituitary adenylate cyclase-activating 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 accumulated 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
TOP
 ABSTRACT
 KEY CHARACTERISTICS OF FETAL...
 TISSUE MEDIATORS OF ACUTE...
 DIRECT VASCULAR EFFECTS OF...
EFFECTS OF CHRONIC HYPOXIA...
 EFFECTS OF CHRONIC HYPOXIA...
 FUTURE DIRECTIONS
 GRANTS
 REFERENCES
 
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 stimulate 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 heterogeneous 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 vasodilatation 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-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 mediate 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 interpretation 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 cerebral 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 more proximal arteries, including the common carotid, maintain 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.


   EFFECTS OF CHRONIC HYPOXIA ON THE FETAL BRAIN
TOP
 ABSTRACT
 KEY CHARACTERISTICS OF FETAL...
 TISSUE MEDIATORS OF ACUTE...
 DIRECT VASCULAR EFFECTS OF...
 EFFECTS OF CHRONIC HYPOXIA...
EFFECTS OF CHRONIC HYPOXIA...
 FUTURE DIRECTIONS
 GRANTS
 REFERENCES
 
Chronic hypoxia produces a pattern of responses very different from those elicited by acute hypoxia. With sustained hypoxia, plasma hemoglobin concentrations rise and blood flows to most fetal organs tend to normalize but with sustained reductions in oxygen delivery to most organs other than the brain and heart (14). Fetal cardiac output is typically depressed by moderate chronic hypoxia, but cerebral blood flow is maintained, as is the vasodilatory response to acute hypoxia (55). Much of this compensation for chronic hypoxia appears to be facilitated by the maternal circulation (20). In contrast, maternal pathologies such as placental insufficiency (90) and hypertension (35) can cause chronic fetal hypoxia, in which cases the fetal compensations for chronic hypoxia can be quite heterogeneous. Chronic fetal hypoxia has been associated with low birth weights (92, 121) and a variety of changes in brain structure, neuronal density, and function (88, 90, 105) as well as a broad range of cerebral pathologies, including increased incidence of intracranial hemorrhage (130) and periventricular leukomalacia (113). Acclimatization to chronic hypoxia during fetal life has also been suggested to have an adverse influence on adult cardiovascular health (9).

Given the range and diversity of clinically relevant fetal responses to chronic hypoxia, a broad variety of studies have focused on how fetal cerebral tissues alter their characteristics in response to chronic hypoxia. Thus chronic hypoxia has been shown to upregulate pontine adenosine receptors (63), suggesting modulation of hypoxia’s ability to inhibit cerebral metabolism. Chronic hypoxia has also been shown to stimulate hypothalamic production of vasopressin and oxytocin (57) and release of atrial and brain natriuretic peptides (59), indicating important potential changes in fetal fluid balance during chronic hypoxia. Other studies have revealed that expression of the enzyme ornithine decarboxylase increases upon exposure to hypoxia with a time to peak response of ~4 h (72, 93). Owing to the key role of ornithine decarboxylase in polyamine synthesis related to growth and differentiation, these studies indicate a fundamental response at the cellular level that may help individual cerebral cells adapt to the demands of chronic hypoxia. Other studies have revealed that chronic hypoxia stimulates the synthesis of the vasodilator adrenomedullin in the fetal cerebral cortex (53), suggesting a mechanism whereby the fetal brain may help maintain adequate oxygen delivery under low-oxygen conditions. The vasodilator peptide calcitonin gene-related peptide also appears to play an important role in fetal adjustments to chronic hypoxia (115), although the exact role of this peptide in the cerebral circulation remains largely unexamined. Without doubt, chronic hypoxia brings about a diverse sequence of adjustments in neuronal and glial protein expression and regulation within the fetal brain (see Fig. 1). How these changes are coordinated and how they influence overall cerebrovascular regulation remain largely unknown.


   EFFECTS OF CHRONIC HYPOXIA ON FETAL CEREBRAL ARTERIES
TOP
 ABSTRACT
 KEY CHARACTERISTICS OF FETAL...
 TISSUE MEDIATORS OF ACUTE...
 DIRECT VASCULAR EFFECTS OF...
 EFFECTS OF CHRONIC HYPOXIA...
 EFFECTS OF CHRONIC HYPOXIA...
FUTURE DIRECTIONS
 GRANTS
 REFERENCES
 
Aside from hypoxic changes in the cerebral parenchyma, it is also clear that chronic hypoxia dramatically alters the composition and reactivity of fetal cerebral arteries. The vasculature of the immature brain is highly plastic and can respond with robust increases in capillary density in response to hypoxia (112). Both vascular endothelial growth factor and erythropoietin are important components of the endocrine response to chronic hypoxia, and in turn these bring about multiple changes of significance for cardiovascular and cerebrovascular regulation (81). Chronic hypoxia increases protein content in fetal cerebral arteries, depresses the magnitude of depolarization-induced contractions, and also depresses the densities of several receptor types that drive contraction in these arteries (71, 120). In turn, inositol trisphosphate mobilization and receptor density are also depressed by chronic hypoxia (131). At the same time, in distal branches of fetal middle cerebral arteries, hypoxia enhances the affinity of 5-HT receptors for serotonin in the neonate (114). Also in fetal middle cerebral arteries, chronic hypoxia appears to attenuate the ability of ATP-sensitive and calcium-sensitive potassium channels to promote relaxation (70). In ovine cerebral arteries, chronic hypoxia downregulates the ability of calcium to promote myosin phosphorylation, but this effect is more than offset by an upregulated ability of phosphorylated myosin to produce force (see Fig. 1). The net effect of these changes is to yield increased myofilament calcium sensitivity in fetal cerebral arteries (89). This upregulated calcium sensitivity may help to preserve the ability of the arteries to contract but with smaller, and possibly more energetically efficient, changes in cytosolic calcium. However, the combination of depressed overall contractility together with decreased potassium channel reactivity indicates that the hypoxic fetus is more delicately balanced between contraction and relaxation than in the normoxic state. Taken together, these adaptations to chronic hypoxia appear prioritized to conserve energy while preserving basic contractility. This untested hypothesis seems a reasonable focus for future investigations of the molecular mechanisms whereby hypoxia is sensed and initiates changes in gene transcription and protein expression leading to hypoxic cerebrovascular adaptation. Equally important, it is clear that cerebral arteries respond very differently to chronic hypoxia in adult and fetal brain, and the mechanistic basis for these marked differences remains largely unexplored.

In many cerebral arteries, the interface between the adventitial and medial layers is supplied by a broad variety of perivascular nerves that exert motor, sensory, and trophic influences on the smooth muscle and endothelium constituents of the artery wall. Not surprisingly, chronic hypoxia changes the function of at least some of these nerves. Chronic hypoxia depresses the function of nitric oxide releasing nerves in the middle cerebral artery, and because these nerves can facilitate norepinephrine release from adrenergic nerves, overall norepinephrine release decreases in chronically hypoxic fetal cerebral arteries (22, 23) (see Fig. 1). This response, which is due to a decrease in the expression of neuronal nitric oxide synthase (nNOS) in the perivascular nitridergic innervation (82), is a unique feature of the fetal response to chronic hypoxia and is absent in adult cerebral arteries. Typically, the adrenergic neurovascular apparatus is less efficient at initiating contraction in fetal compared with adult middle cerebral arteries (98), but chronic hypoxia appears to upregulate the ability of adrenergic stimulation to initiate contraction in fetal cerebral arteries (41, 73, 74). This effect, combined with the reduced norepinephrine release produced by hypoxic acclimatization in fetal arteries, suggests important changes in synaptic structure and/or function (such as reduced synaptic cleft width or reduced reuptake efficiency) that enable a smaller mass of norepinephrine to yield a stronger contraction, despite postsynaptic downregulation. Again this is a largely untested hypothesis 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 phenotype 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 hypoxia 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-dependent 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
TOP
 ABSTRACT
 KEY CHARACTERISTICS OF FETAL...
 TISSUE MEDIATORS OF ACUTE...
 DIRECT VASCULAR EFFECTS OF...
 EFFECTS OF CHRONIC HYPOXIA...
 EFFECTS OF CHRONIC HYPOXIA...
 FUTURE DIRECTIONS
GRANTS
 REFERENCES
 
As is common in fetal physiology, understanding and appreciation 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 hypoxia, 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 oxygenation can precipitate multiple long-lasting disturbances of the cerebral circulation with potentially hypoxic consequences (36, 44).

Regarding the fetal consequences of chronic hypoxia, it has long been recognized that fetal hypoxemia is strongly associated 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 conditioning 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 cerebrovascular 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 direct effects of hypoxia on the smooth muscle and endothelium 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 opportunities 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 measurements 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 powerful 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 demonstrated that hypoxia can dramatically increase the lactate-to-creatine ratio in cerebral tissue over a time course that correlates 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 cardiovascular and metabolic side effects of many conventional therapies used clinically to manage the posthypoxic fetus (68, 87).


   GRANTS
TOP
 ABSTRACT
 KEY CHARACTERISTICS OF FETAL...
 TISSUE MEDIATORS OF ACUTE...
 DIRECT VASCULAR EFFECTS OF...
 EFFECTS OF CHRONIC HYPOXIA...
 EFFECTS OF CHRONIC HYPOXIA...
 FUTURE DIRECTIONS
 GRANTS
REFERENCES
 
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.


   FOOTNOTES
 

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{at}llu.edu)


   REFERENCES
TOP
 ABSTRACT
 KEY CHARACTERISTICS OF FETAL...
 TISSUE MEDIATORS OF ACUTE...
 DIRECT VASCULAR EFFECTS OF...
 EFFECTS OF CHRONIC HYPOXIA...
 EFFECTS OF CHRONIC HYPOXIA...
 FUTURE DIRECTIONS
 GRANTS
 REFERENCES
 

  1. Aguan K, Murotsuki J, Gagnon R, Thompson LP, and Weiner CP. Effect of chronic hypoxemia on the regulation of nitric-oxide synthase in the fetal sheep brain. Brain Res Dev Brain Res 111: 271–277, 1998.[Medline]
  2. Angeles DM, Williams J, Purdy RE, Zhang L, and Pearce WJ. Effects of maturation and acute hypoxia on receptor-IP3 coupling in ovine common carotid arteries. Am J Physiol Regul Integr Comp Physiol 280: R410–R417, 2001.[Abstract/Free Full Text]
  3. Angeles DM, Williams J, Zhang L, and Pearce WJ. Acute hypoxia modulates 5-HT receptor density and agonist affinity in fetal and adult ovine carotid arteries. Am J Physiol Heart Circ Physiol 279: H502–H510, 2000.[Abstract/Free Full Text]
  4. Arbeille P, Maulik D, Fignon A, Stale H, Berson M, Bodard S, and Locatelli A. Assessment of the fetal PO2 changes by cerebral and umbilical Doppler on lamb fetuses during acute hypoxia. Ultrasound Med Biol 21: 861–870, 1995.[CrossRef][Web of Science][Medline]
  5. Armstead WM. Opioids and nitric oxide contribute to hypoxia-induced pial arterial vasodilation in newborn pigs. Am J Physiol Heart Circ Physiol 268: H226–H232, 1995.[Abstract/Free Full Text]
  6. Armstead WM. Role of activation of calcium-sensitive K+ channels in NO- and hypoxia-induced pial artery vasodilation. Am J Physiol Heart Circ Physiol 272: H1785–H1790, 1997.[Abstract/Free Full Text]
  7. Armstead WM. Stimulus duration modulates the interaction between opioids and nitric oxide in hypoxic pial artery dilation. Brain Res 825: 68–74, 1999.[CrossRef][Web of Science][Medline]
  8. Bari F, Errico RA, Louis TM, and Busija DW. Differential effects of short-term hypoxia and hypercapnia on N-methyl-D-aspartate-induced cerebral vasodilatation in piglets. Stroke 27: 1634–1639; discussion 1639–1640, 1996.[Abstract/Free Full Text]
  9. Barker DJ and Hanson MA. Altered regional blood flow in the fetus: the origins of cardiovascular disease? Acta Paediatr 93: 1559–1560, 2004.[CrossRef][Web of Science][Medline]
  10. Barr LL, McCullough PJ, Ball WS Jr, Krasner BH, Garra BS, and Deddens JA. Quantitative sonographic feature analysis of clinical infant hypoxia: a pilot study. AJNR Am J Neuroradiol 17: 1025–1031, 1996.[Abstract]
  11. Bauer R, Zwiener U, Buchenau W, Hoyer D, Witte H, Lampe V, Burgold K, and Zieger M. Restricted cardiovascular and cerebral performance of intra-uterine growth retarded newborn piglets during severe hypoxia. Biomed Biochim Acta 48: 697–705, 1989.[Web of Science][Medline]
  12. Bernert G, von Siebenthal K, Kohlhauser C, and Casaer P. Near infrared spectroscopy: methodological principles and clinical application in preterm infants. Wien Klin Wochenschr 107: 569–573, 1995.[Web of Science][Medline]
  13. Bernstein D, Teitel D, Sidi D, Heymann MA, and Rudolph AM. Redistribution of regional blood flow and oxygen delivery in experimental cyanotic heart disease in newborn lambs. Pediatr Res 22: 389–393, 1987.[Web of Science][Medline]
  14. Bernstein D, Teitel DF, and Rudolph AM. Chronic anemia in the newborn lamb: cardiovascular adaptations and comparison to chronic hypoxemia. Pediatr Res 23: 621–627, 1988.[Web of Science][Medline]
  15. Bilger A and Nehlig A. Regional cerebral blood flow response to acute hypoxia changes with postnatal age in the rat. Brain Res Dev Brain Res 76: 197–205, 1993.[CrossRef][Medline]
  16. Binienda Z, Fogle CM, Slikker W Jr, and Ali SF. Acute effects of perinatal hypoxic insult on concentrations of dopamine, serotonin, and metabolites in fetal monkey brain. Int J Dev Neurosci 12: 127–131, 1994.[CrossRef][Web of Science][Medline]
  17. Bishai JM, Blood AB, Hunter CJ, Longo LD, and Power GG. Fetal lamb cerebral blood flow (CBF) and oxygen tensions during hypoxia: a comparison of laser Doppler and microsphere measurements of CBF. J Physiol 546: 869–878, 2003.[Abstract/Free Full Text]
  18. Blood AB, Hunter CJ, and Power GG. The role of adenosine in regulation of cerebral blood flow during hypoxia in the near-term fetal sheep. J Physiol 543: 1015–1023, 2002.[Abstract/Free Full Text]
  19. Blood AB, Hunter CJ, and Power GG. Adenosine mediates decreased cerebral metabolic rate and increased cerebral blood flow during acute moderate hypoxia in the near-term fetal sheep. J Physiol 553: 935–945, 2003.[Abstract/Free Full Text]
  20. Bocking AD, Gagnon R, White SE, Homan J, Milne KM, and Richardson BS. Circulatory responses to prolonged hypoxemia in fetal sheep. Am J Obstet Gynecol 159: 1418–1424, 1988.[Web of Science][Medline]
  21. Borowska-Matwiejczuk K, Lemancewicz A, Tarasow E, Urban J, Urban R, Walecki J, and Kubas B. Assessment of fetal distress based on magnetic resonance examinations: preliminary report. Acad Radiol 10: 1274–1282, 2003.[CrossRef][Web of Science][Medline]
  22. Buchholz J and Duckles SP. Chronic hypoxia alters prejunctional {alpha}2-receptor function in vascular adrenergic nerves of adult and fetal sheep. Am J Physiol Regul Integr Comp Physiol 281: R926–R934, 2001.[Abstract/Free Full Text]
  23. Buchholz J, Edwards-Teunissen K, and Duckles SP. Impact of development and chronic hypoxia on NE release from adrenergic nerves in sheep arteries. Am J Physiol Regul Integr Comp Physiol 276: R799–R808, 1999.[Abstract/Free Full Text]
  24. Cai Z, Hutchins JB, and Rhodes PG. Intrauterine hypoxia-ischemia alters nitric oxide synthase expression and activity in fetal and neonatal rat brains. Brain Res Dev Brain Res 109: 265–269, 1998.[CrossRef][Medline]
  25. Cai Z, Xiao F, Lee B, Paul IA, and Rhodes PG. Prenatal hypoxia-ischemia alters expression and activity of nitric oxide synthase in the young rat brain and causes learning deficits. Brain Res Bull 49: 359–365, 1999.[CrossRef][Web of Science][Medline]
  26. Cavazzuti M and Duffy TE. Regulation of local cerebral blood flow in normal and hypoxic newborn dogs. Ann Neurol 11: 247–257, 1982.[CrossRef][Web of Science][Medline]
  27. Chihara H, Blood AB, Hunter CJ, and Power GG. Effect of mild hypothermia and hypoxia on blood flow and oxygen consumption of the fetal sheep brain. Pediatr Res 54: 665–671, 2003.[CrossRef][Web of Science][Medline]
  28. Clapp JF 3rd, Mann LI, Peress NS, and Szeto HH. Neuropathology in the chronic fetal lamb preparation: structure-function correlates under different environmental conditions. Am J Obstet Gynecol 141: 973–986, 1981.[Web of Science][Medline]
  29. Corbett RJ. In vivo multinuclear magnetic resonance spectroscopy investigations of cerebral development and metabolic encephalopathy using neonatal animal models. Semin Perinatol 14: 258–271, 1990.[Web of Science][Medline]
  30. Cornfield DN, Stevens T, McMurtry IF, Abman SH, and Rodman DM. Acute hypoxia causes membrane depolarization and calcium influx in fetal pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 266: L469–L475, 1994.[Abstract/Free Full Text]
  31. Coumans AB, Garnier Y, Supcun S, Jensen A, Hasaart TH, and Berger R. The role of nitric oxide on fetal cardiovascular control during normoxia and acute hypoxia in 0.75 gestation sheep. J Soc Gynecol Investig 10: 275–282, 2003.[CrossRef][Web of Science][Medline]
  32. Covello KL and Simon MC. HIFs, hypoxia, and vascular development. Curr Top Dev Biol 62: 37–54, 2004.[Web of Science][Medline]
  33. Darnall RA, Green G, Pinto L, and Hart N. Effect of acute hypoxia on respiration and brain stem blood flow in the piglet. J Appl Physiol 70: 251–259, 1991.[Abstract/Free Full Text]
  34. Daven JR, Milstein JM, and Guthrie RD. Cerebral vascular resistance in premature infants. Am J Dis Child 137: 328–331, 1983.[Abstract/Free Full Text]
  35. Dubiel M, Gunnarsson GO, and Gudmundsson S. Blood redistribution in the fetal brain during chronic hypoxia. Ultrasound Obstet Gynecol 20: 117–121, 2002.[CrossRef][Web of Science][Medline]
  36. Ferry PC. Neurologic sequelae of cardiac surgery in children. Am J Dis Child 141: 309–312, 1987.[Abstract/Free Full Text]
  37. Firbank M, Elwell CE, Cooper CE, and Delpy DT. Experimental and theoretical comparison of NIR spectroscopy measurements of cerebral hemoglobin changes. J Appl Physiol 85: 1915–1921, 1998.[Abstract/Free Full Text]
  38. Galleguillos M, Valenzuela MA, Riquelme R, Sanhueza E, Sanchez G, Figueroa JP, and Llanos AJ. Nitric oxide synthase activity in brain tissues from llama fetuses submitted to hypoxemia. Comp Biochem Physiol A 129: 605–614, 2001.[CrossRef][Medline]
  39. Gavilanes AW, Vles JS, von Siebenthal K, van Sprundel R, Reulen JP, and Blanco CE. Neonatal electrocortical brain activity and cerebral tissue oxygenation during non-acidotic, normocarbic and normotensive graded hypoxemia. Clin Neurophysiol 115: 282–288, 2004.[CrossRef][Web of Science][Medline]
  40. Gilbert RD, Pearce WJ, Ashwal S, and Longo LD. Effects of hypoxia on contractility of isolated fetal lamb cerebral arteries. J Dev Physiol 13: 199–203, 1990.[Web of Science][Medline]
  41. Gilbert RD, Pearce WJ, and Longo LD. Fetal cardiac and cerebrovascular acclimatization responses to high altitude, long-term hypoxia. High Alt Med Biol 4: 203–213, 2003.[CrossRef][Medline]
  42. Gleason CA, Hamm C, and Jones MD Jr. Effect of acute hypoxemia on brain blood flow and oxygen metabolism in immature fetal sheep. Am J Physiol Heart Circ Physiol 258: H1064–H1069, 1990.[Abstract/Free Full Text]
  43. Gleason CA, Iida H, Hotchkiss KJ, Northington FJ, and Traystman RJ. Newborn cerebrovascular responses after first trimester moderate maternal ethanol exposure in sheep. Pediatr Res 42: 39–45, 1997.[Web of Science][Medline]
  44. Graziani LJ, Streletz LJ, Mitchell DG, Merton DA, Kubichek M, Desai HJ, and McKee L. Electroencephalographic, neuroradiologic, and neurodevelopmental studies in infants with subclavian steal during ECMO. Pediatr Neurol 10: 97–103, 1994.[CrossRef][Web of Science][Medline]
  45. Green GA, Darnall RA, Bierd TB, and Adams JM. Effect of aortic balloon inflation on ventilation and brain stem blood flow in piglets. J Appl Physiol 66: 2174–2180, 1989.[Abstract/Free Full Text]
  46. Harris AP, Helou S, Gleason CA, Traystman RJ, and Koehler RC. Fetal cerebral and peripheral circulatory responses to hypoxia after nitric oxide synthase inhibition. Am J Physiol Regul Integr Comp Physiol 281: R381–R390, 2001.[Abstract/Free Full Text]
  47. Herrera EA, Riquelme RA, Sanhueza EM, Gajardo C, Parer JT, and Llanos AJ. Cardiovascular responses to arginine vasopressin blockade during acute hypoxemia in the llama fetus. High Alt Med Biol 1: 175–184, 2000.[CrossRef][Medline]
  48. Hill A. Current concepts of hypoxic-ischemic cerebral injury in the term newborn. Pediatr Neurol 7: 317–325, 1991.[CrossRef][Web of Science][Medline]
  49. Hu H and Jin X. [Role of sensory neuropeptides in the responses of pulmonary and cerebral blood vessels to acute hypoxia in rats]. Zhonghua Yi Xue Za Zhi 76: 104–108, 1996.[Medline]
  50. Hunter CJ, Blood AB, White CR, Pearce WJ, and Power GG. Role of nitric oxide in hypoxic cerebral vasodilatation in the ovine fetus. J Physiol 549: 625–633, 2003.[Abstract/Free Full Text]
  51. Itskovitz J, LaGamma EF, Bristow J, and Rudolph AM. Cardiovascular responses to hypoxemia in sinoaortic-denervated fetal sheep. Pediatr Res 30: 381–385, 1991.[Web of Science][Medline]
  52. Jensen A, Garnier Y, and Berger R. Dynamics of fetal circulatory responses to hypoxia and asphyxia. Eur J Obstet Gynecol Reprod Biol 84: 155–172, 1999.[CrossRef][Web of Science][Medline]
  53. Jensen RI, Carter AM, Skott O, and Jensen BL. Adrenomedullin expression during hypoxia in fetal sheep. Acta Physiol Scand 183: 219–228, 2005.[CrossRef][Web of Science][Medline]
  54. Joseph SA and Walker DW. Monoamine concentrations in cerebrospinal fluid of fetal and newborn sheep. Am J Physiol Regul Integr Comp Physiol 266: R472–R480, 1994.[Abstract/Free Full Text]
  55. Kamitomo M, Alonso JG, Okai T, Longo LD, and Gilbert RD. Effects of long-term, high-altitude hypoxemia on ovine fetal cardiac output and blood flow distribution. Am J Obstet Gynecol 169: 701–707, 1993.[Web of Science][Medline]
  56. Kara T, Narkiewicz K, and Somers VK. Chemoreflexes—physiology and clinical implications. Acta Physiol Scand 177: 377–384, 2003.[CrossRef][Web of Science][Medline]
  57. Kelestimur H, Leach RM, Ward JP, and Forsling ML. Vasopressin and oxytocin release during prolonged environmental hypoxia in the rat. Thorax 52: 84–88, 1997.[Abstract/Free Full Text]
  58. Kietzmann T, Knabe W, and Schmidt-Kastner R. Hypoxia and hypoxia-inducible factor modulated gene expression in brain: involvement in neuroprotection and cell death. Eur Arch Psychiatry Clin Neurosci 251: 170–178, 2001.[CrossRef][Web of Science][Medline]
  59. Klinger JR, Siddiq FM, Swift RA, Jackson C, Pietras L, Warburton RR, Alia C, and Hill NS. C-type natriuretic peptide expression and pulmonary vasodilation in hypoxia-adapted rats. Am J Physiol Lung Cell Mol Physiol 275: L645–L652, 1998.[Abstract/Free Full Text]
  60. Koehler RC, Traystman RJ, and Jones MD Jr. Regional blood flow and O2 transport during hypoxic and CO hypoxia in neonatal and adult sheep. Am J Physiol Heart Circ Physiol 248: H118–H124, 1985.[Abstract/Free Full Text]
  61. Koehler RC, Traystman RJ, Zeger S, Rogers MC, and Jones MD Jr. Comparison of cerebrovascular response to hypoxic and carbon monoxide hypoxia in newborn and adult sheep. J Cereb Blood Flow Metab 4: 115–122, 1984.[Web of Science][Medline]
  62. Koos BJ, Mason BA, Punla O, and Adinolfi AM. Hypoxic inhibition of breathing in fetal sheep: relationship to brain adenosine concentrations. J Appl Physiol 77: 2734–2739, 1994.[Abstract/Free Full Text]
  63. Koos BJ, Murray TF, and Doany W. Anemia up-regulates pontine A1 adenosine receptors in fetal sheep. Brain Res 579: 291–295, 1992.[CrossRef][Web of Science][Medline]
  64. Krampl E, Chalubinski K, Schatten C, and Husslein P. Does acute hypoxia cause fetal arterial blood flow redistribution? Ultrasound Obstet Gynecol 18: 175–177, 2001.[CrossRef][Web of Science][Medline]
  65. Kurth CD and Wagerle LC. Cerebrovascular reactivity to adenosine analogues in 0.6–07 gestation and near-term fetal sheep. Am J Physiol Heart Circ Physiol 262: H1338–H1342, 1992.[Abstract/Free Full Text]
  66. Lan J, Hunter CJ, Murata T, and Power GG. Adaptation of laser-Doppler flowmetry to measure cerebral blood flow in the fetal sheep. J Appl Physiol 89: 1065–1071, 2000.[Abstract/Free Full Text]
  67. Leffler CW and Parfenova H. Cerebral arteriolar dilation to hypoxia: role of prostanoids. Am J Physiol Heart Circ Physiol 272: H418–H424, 1997.[Abstract/Free Full Text]
  68. Levene MI, Gibson NA, Fenton AC, Papathoma E, and Barnett D. The use of a calcium-channel blocker, nicardipine, for severely asphyxiated newborn infants. Dev Med Child Neurol 32: 567–574, 1990.[Web of Science][Medline]
  69. Llanos AJ, Riquelme RA, Sanhueza EM, Hanson MA, Blanco CE, Parer JT, Herrera EA, Pulgar VM, Reyes RV, Cabello G, and Giussani DA. The fetal llama versus the fetal sheep: different strategies to withstand hypoxia. High Alt Med Biol 4: 193–202, 2003.[CrossRef][Medline]
  70. Long W, Zhang L, and Longo LD. Fetal and adult cerebral artery KATP and KCa channel responses to long-term hypoxia. J Appl Physiol 92: 1692–1701, 2002.[Abstract/Free Full Text]
  71. Longo LD, Hull AD, Long DM, and Pearce WJ. Cerebrovascular adaptations to high-altitude hypoxemia in fetal and adult sheep. Am J Physiol Regul Integr Comp Physiol 264: R65–R72, 1993.[Abstract/Free Full Text]
  72. Longo LD, Packianathan S, McQueary JA, Stagg RB, Byus CV, and Cain CD. Acute hypoxia increases ornithine decarboxylase activity and polyamine concentrations in fetal rat brain. Proc Natl Acad Sci USA 90: 692–696, 1993.[Abstract/Free Full Text]
  73. Longo LD and Pearce WJ. High altitude, hypoxic-induced modulation of noradrenergic-mediated responses in fetal and adult cerebral arteries. Comp Biochem Physiol A 119: 683–694, 1998.[CrossRef][Medline]
  74. Longo LD and Pearce WJ. Fetal cerebrovascular acclimatization responses to high-altitude, long-term hypoxia: a model for prenatal programming of adult disease? Am J Physiol Regul Integr Comp Physiol 288: R16–R24, 2005.[Abstract/Free Full Text]
  75. Lorek A, Takei Y, Cady EB, Wyatt JS, Penrice J, Edwards AD, Peebles D, Wylezinska M, Owen-Reece H, and Kirkbride V. Delayed ("secondary") cerebral energy failure after acute hypoxia-ischemia in the newborn piglet: continuous 48-hour studies by phosphorus magnetic resonance spectroscopy. Pediatr Res 36: 699–706, 1994.[Web of Science][Medline]
  76. Lou HC. Perinatal hypoxic-ischemic brain damage and intraventricular hemorrhage. A pathogenetic model. Arch Neurol 37: 585–587, 1980.[Abstract/Free Full Text]
  77. Low JA. The relationship of asphyxia in the mature fetus to long-term neurologic function. Clin Obstet Gynecol 36: 82–90, 1993.[CrossRef][Web of Science][Medline]
  78. Lutz PL. Mechanisms for anoxic survival in the vertebrate brain. Annu Rev Physiol 54: 601–618, 1992.[CrossRef][Web of Science][Medline]
  79. Mallard EC, Rees S, Stringer M, Cock ML, and Harding R. Effects of chronic placental insufficiency on brain development in fetal sheep. Pediatr Res 43: 262–270, 1998.[Web of Science][Medline]
  80. Mann LI. Pregnancy events and brain damage. Am J Obstet Gynecol 155: 6–9, 1986.[Web of Science][Medline]
  81. Marti HH. Erythropoietin and the hypoxic brain. J Exp Biol 207: 3233–3242, 2004.[Abstract/Free Full Text]
  82. Mbaku EM, Zhang L, Pearce WJ, Duckles SP, and Buchholz J. Chronic hypoxia alters the function of NOS nerves in cerebral arteries of near-term fetal and adult sheep. J Appl Physiol 94: 724–732, 2003.[Abstract/Free Full Text]
  83. Mei X and Gu Z. [Prostacyclin participates in regulation of hypoxic and high CO2 cerebrovascular tension]. Zhongguo Ying Yong Sheng Li Xue Za Zhi 13: 29–31, 1997.[Medline]
  84. Ment LR, Stewart WB, Duncan CC, Pitt BR, and Cole JS. Beagle puppy model of perinatal cerebral infarction. Regional cerebral prostaglandin changes during acute hypoxemia. J Neurosurg 65: 851–855, 1986.[Web of Science][Medline]
  85. Meschia G. Evolution of thinking in fetal respiratory physiology. Am J Obstet Gynecol 132: 806–813, 1978.[Web of Science][Medline]
  86. Moore LG, Niermeyer S, and Zamudio S. Human adaptation to high altitude: regional and life-cycle perspectives. Am J Phys Anthropol 27, Suppl: 25–64, 1998.[Medline]
  87. Munkeby BH, Borke WB, Bjornland K, Sikkeland LI, Borge GI, Halvorsen B, and Saugstad OD. Resuscitation with 100% O2 increases cerebral injury in hypoxemic piglets. Pediatr Res 56: 783–790, 2004.[CrossRef][Web of Science][Medline]
  88. Naeye RL. Brain-stem and adrenal abnormalities in the sudden-infant-death syndrome. Am J Clin Pathol 66: 526–530, 1976.[Web of Science][Medline]
  89. Nauli SM, Williams JM, Gerthoffer WT, and Pearce WJ. Chronic hypoxia modulates relations among calcium, myosin light chain phosphorylation, and force differently in fetal and adult ovine basilar arteries. J Appl Physiol 99: 120–127, 2005.[Abstract/Free Full Text]
  90. Nicholls T, Lacey B, Nitsos I, Smythe G, and Walker DW. Regional changes in kynurenic acid, quinolinic acid, and glial fibrillary acidic protein concentrations in the fetal sheep brain after experimentally induced placental insufficiency. Am J Obstet Gynecol 184: 203–208, 2001.[CrossRef][Web of Science][Medline]
  91. Okamura T, Ayajiki K, and Toda N. Hypoxia-induced inhibition of the response to nitroxidergic nerve stimulation in canine cerebral arteries. J Cereb Blood Flow Metab 17: 807–813, 1997.[CrossRef][Web of Science][Medline]
  92. Pachi A, Lubrano R, Maggi E, Giancotti A, Giampa G, Elli M, Mannarino O, and Castello MA. Renal tubular damage in fetuses with intrauterine growth retardation. Fetal Diagn Ther 8: 109–113, 1993.[Web of Science][Medline]
  93. Packianathan S, Cain CD, Stagg RB, and Longo LD. Ornithine decarboxylase activity in fetal and newborn rat brain: responses to hypoxic and carbon monoxide hypoxia. Brain Res Dev Brain Res 76: 131–140, 1993.[CrossRef][Medline]
  94. Park TS, Van Wylen DG, Rubio R, and Berne RM. Increased brain interstitial fluid adenosine concentration during hypoxia in newborn piglet. J Cereb Blood Flow Metab 7: 178–183, 1987.[Web of Science][Medline]
  95. Pearce WJ. Mechanisms of hypoxic cerebral vasodilatation. Pharmacol Ther 65: 75–91, 1995.[CrossRef][Web of Science][Medline]
  96. Pearce WJ and Ashwal S. Developmental changes in thickness, contractility, and hypoxic sensitivity of newborn lamb cerebral arteries. Pediatr Res 22: 192–196, 1987.[Web of Science][Medline]
  97. Pearce WJ, Ashwal S, and Cuevas J. Direct effects of graded hypoxia on intact and denuded rabbit cranial arteries. Am J Physiol Heart Circ Physiol 257: H824–H833, 1989.[Abstract/Free Full Text]
  98. Pearce WJ, Duckles SP, and Buchholz J. Effects of maturation on adrenergic neurotransmission in ovine cerebral arteries. Am J Physiol Regul Integr Comp Physiol 277: R931–R937, 1999.[Abstract/Free Full Text]
  99. Pearce WJ and Longo LD. Developmental aspects of endothelial function. Semin Perinatol 15: 40–48, 1991.[Web of Science][Medline]
  100. Penrice J, Lorek A, Cady EB, Amess PN, Wylezinska M, Cooper CE, D’Souza P, Brown GC, Kirkbride V, Edwards AD, Wyatt JS, and Reynolds EO. Proton magnetic resonance spectroscopy of the brain during acute hypoxia-ischemia and delayed cerebral energy failure in the newborn piglet. Pediatr Res 41: 795–802, 1997.[Web of Science][Medline]
  101. Polvi HJ, Pirhonen JP, and Erkkola RU. The hemodynamic effects of maternal hypo- and hyperoxygenation in healthy term pregnancies. Obstet Gynecol 86: 795–799, 1995.[CrossRef][Web of Science][Medline]
  102. Pryds O. Low neonatal cerebral oxygen delivery is associated with brain injury in preterm infants. Acta Paediatr 83: 1233–1236, 1994.[Web of Science][Medline]
  103. Raju TN, Bhat R, and Vidyasagar D. Age-related difference in cerebral perfusion pressure response to acute hypoxia in neonatal puppies. Biol Neonate 41: 258–264, 1982.[Web of Science][Medline]
  104. Richardson B, Korkola S, Asano H, Challis J, Polk D, and Fraser M. Regional blood flow and the endocrine response to sustained hypoxemia in the preterm ovine fetus. Pediatr Res 40: 337–343, 1996.[Web of Science][Medline]
  105. Romijn HJ, van Marle J, and Janszen AW. Permanent increase of the GAD67/synaptophysin ratio in rat cerebral cortex nerve endings as a result of hypoxic ischemic encephalopathy sustained in early postnatal life: a confocal laser scanning microscopic study. Brain Res 630: 315–329, 1993.[CrossRef][Web of Science][Medline]
  106. Rosenberg AA. Regulation of cerebral blood flow after asphyxia in neonatal lambs. Stroke 19: 239–244, 1988.[Abstract/Free Full Text]
  107. Rossberg MI and Armstead WM. Relationship between vasopressin and opioids in hypoxia induced pial artery vasodilation. Am J Physiol Heart Circ Physiol 271: H521–H527, 1996.[Abstract/Free Full Text]
  108. Ruijtenbeek K, Kessels LC, De Mey JG, and Blanco CE. Chronic moderate hypoxia and protein malnutrition both induce growth retardation, but have distinct effects on arterial endothelium-dependent reactivity in the chicken embryo. Pediatr Res 53: 573–579, 2003.[CrossRef][Web of Science][Medline]
  109. Savel’eva GM, Chekhonin VP, Pavlova TA, Kushch IB, Shalina RI, Rogatkin SO, Morozov SG, and Volodin NN. [An immunochemical analysis of the function of the hemato-encephalic barrier in acute fetal hypoxia and asphyxia neonatorum]. Akush Ginekol (Mosk): 43–46, 1991.
  110. Senat MV, Schwarzler P, Alcais A, and Ville Y. Longitudinal changes in the ductus venosus, cerebral transverse sinus and cardiotocogram in fetal growth restriction. Ultrasound Obstet Gynecol 16: 19–24, 2000.[Web of Science][Medline]
  111. Sharp FR, Bergeron M, and Bernaudin M. Hypoxia-inducible factor in brain. Adv Exp Med Biol 502: 273–291, 2001.[Web of Science][Medline]
  112. Shewmon DA, Fine M, Masdeu JC, and Palacios E. Postischemic hypervascularity of infancy: a stage in the evolution of ischemic brain damage with characteristic CT scan. Ann Neurol 9: 358–365, 1981.[CrossRef][Web of Science][Medline]
  113. Tamisari L, Vigi V, Fortini C, and Scarpa P. Neonatal periventricular leukomalacia: diagnosis and evolution evaluated by real-time ultrasound. Helv Paediatr Acta 41: 399–407, 1986.[Web of Science][Medline]
  114. Teng GQ, Williams J, Zhang L, Purdy R, and Pearce WJ. Effects of maturation, artery size, and chronic hypoxia on 5-HT receptor type in ovine cranial arteries. Am J Physiol Regul Integr Comp Physiol 275: R742–R753, 1998.[Abstract/Free Full Text]
  115. Thakor AS and Giussani DA. Calcitonin gene-related peptide contributes to the umbilical haemodynamic defence response to acute hypoxaemia. J Physiol 563: 309–317, 2005.[Abstract/Free Full Text]
  116. Thomas T and Marshall JM. A study on rats of the effects of chronic hypoxia from birth on respiratory and cardiovascular responses evoked by acute hypoxia. J Physiol 487: 513–525, 1995.[Abstract/Free Full Text]
  117. Tobal N, Chevillot M, Himily V, Perrotin F, Lansac J, and Arbeille P. [Doppler monitoring of fetal circulation from multiple arteries over several days to improve evaluation of fetal prognosis]. J Radiol 83: 1943–1951, 2002.[Web of Science][Medline]
  118. Tolcos M, Harding R, Loeliger M, Breen S, Cock M, Duncan J, and Rees S. The fetal brainstem is relatively spared from injury following intrauterine hypoxemia. Brain Res Dev Brain Res 143: 73–81, 2003.[CrossRef][Medline]
  119. Trescher WH, Lehman RA, and Vannucci RC. The influence of growth retardation on perinatal hypoxic-ischemic brain damage. Early Hum Dev 21: 165–173, 1990.[CrossRef][Web of Science][Medline]
  120. Ueno N, Zhao Y, Zhang L, and Longo LD. High altitude-induced changes in alpha1-adrenergic receptors and Ins(1,4,5)P3 responses in cerebral arteries. Am J Physiol Regul Integr Comp Physiol 272: R669–R674, 1997.[Abstract/Free Full Text]
  121. Van Bel F, van de Bor M, Stijnen T, and Ruys JH. Decreased cerebrovascular resistance in small for gestational age infants. Eur J Obstet Gynecol Reprod Biol 23: 137–144, 1986.[CrossRef][Web of Science][Medline]
  122. Wedegartner U, Tchirikov M, Koch M, Adam G, and Schroder H. Functional magnetic resonance imaging (fMRI) for fetal oxygenation during maternal hypoxia: initial results. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 174: 700–703, 2002.[Web of Science][Medline]
  123. White CR, Hamade MW, Siami K, Chang MM, Mangalwadi A, Frangos JA, and Pearce WJ. Maturation enhances fluid shear-induced activation of eNOS in perfused ovine carotid arteries. Am J Physiol Heart Circ Physiol 289: H2220–H2227, 2005.[Abstract/Free Full Text]
  124. Whorton A, Simonds D, and Piantadosi C. Regulation of nitric oxide synthesis by oxygen in vascular endothelial cells. Am J Physiol Lung Cell Mol Physiol 272: L1161–L1166, 1997.[Abstract/Free Full Text]
  125. Wilderman MJ and Armstead WM. Relationship between nitric oxide and opioids in hypoxia-induced pial artery vasodilation. Am J Physiol Heart Circ Physiol 270: H869–H874, 1996.[Abstract/Free Full Text]
  126. Wilderman MJ and Armstead WM. Role of neuronal NO synthase in relationship between NO and opioids in hypoxia-induced pial artery dilation. Am J Physiol Heart Circ Physiol 273: H1807–H1815, 1997.[Abstract/Free Full Text]
  127. Wilderman MJ and Armstead WM. Role of PACAP in the relationship between cAMP and opioids in hypoxia-induced pial artery vasodilation. Am J Physiol Heart Circ Physiol 272: H1350–H1358, 1997.[Abstract/Free Full Text]
  128. Wyatt JS, Edwards AD, Azzopardi D, and Reynolds EO. Magnetic resonance and near infrared spectroscopy for investigation of perinatal hypoxic-ischaemic brain injury. Arch Dis Child 64: 953–963, 1989.[Abstract/Free Full Text]
  129. Yakubu MA, Pourcyrous M, Randolph MM, Blaho KE, Mandrell TD, Bada HS, and Leffler CW. Consequences of maternal cocaine on cerebral microvascular functions in piglets. Brain Res 947: 174–181, 2002.[CrossRef][Web of Science][Medline]
  130. Yoshioka H, Iino S, Sato N, Osamura T, Hasegawa K, Ochi M, Sawada T, and Kusunoki T. New model of hemorrhagic hypoxic-ischemic encephalopathy in newborn mice. Pediatr Neurol 5: 221–225, 1989.[CrossRef][Web of Science][Medline]
  131. Zhou L, Zhao Y, Nijland R, Zhang L, and Longo LD. Ins(1,4,5)P3 receptors in cerebral arteries: changes with development and high-altitude hypoxia. Am J Physiol Regul Integr Comp Physiol 272: R1954–R1959, 1997.[Abstract/Free Full Text]
  132. Zurcher SD, Ong-Veloso GL, Akopov SE, and Pearce WJ. Maturational modification of hypoxic relaxation in ovine carotid and cerebral arteries: role of endothelium. Biol Neonate 74: 222–232, 1998.[CrossRef][Web of Science][Medline]
  133. Zwiener U, Bauer R, Buchenau W, Hoyer D, Zieger M, and Wagner H. Vascular resistance, metabolism and EEG within cerebral grey and white matter during hypoxia in neonatal piglets. Biol Res Pregnancy Perinatol 7: 23–29, 1986.[Web of Science][Medline]



This article has been cited by other articles:


Home page
 Cereb CortexHome page
D. Stubbs, J. DeProto, K. Nie, C. Englund, I. Mahmud, R. Hevner, and Z. Molnar
Neurovascular Congruence during Cerebral Cortical Development
Cereb Cortex, July 1, 2009; 19(suppl_1): i32 - i41.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
Z. Zhang, F. Xu, C. Zhang, and X. Liang
Activation of opioid {micro}-receptors in medullary raphe depresses sighs
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2009; 296(5): R1528 - R1537.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
S. Y. S. Feng, D. J. Phillips, E. M. Stockx, V. Y. H. Yu, and A. M. Walker
Endotoxin has acute and chronic effects on the cerebral circulation of fetal sheep
Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2009; 296(3): R640 - R650.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
C. Torres-Farfan, F. J. Valenzuela, M. Mondaca, G. J. Valenzuela, B. Krause, E. A. Herrera, R. Riquelme, A. J. Llanos, and M. Seron-Ferre
Evidence of a role for melatonin in fetal sheep physiology: direct actions of melatonin on fetal cerebral artery, brown adipose tissue and adrenal gland
J. Physiol., August 15, 2008; 586(16): 4017 - 4027.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
R. J. Sandoval, E. R. Injeti, J. M. Williams, W. T. Georthoffer, and W. J. Pearce
Myogenic contractility is more dependent on myofilament calcium sensitization in term fetal than adult ovine cerebral arteries
Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H548 - H556.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pearce, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pearce, W.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2006 by the American Physiological Society.