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1 Laboratorio de Neurociencias, Departamento de Medicina, Universidad Peruana Cayetano Heredia, Lima, Peru; and Departments of 2 Neurology and Neurological Surgery and 3 Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX
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The effect of chronic hypobaric hypoxia (28 days, 455 Torr) on the organization of brain vessels was studied in Balb/c mice. In comparison to age-matched controls kept at sea level, emulsion-perfused capillaries in hypoxic mice showed marked dilation in all brain areas studied. Capillary length per unit volume of tissue (Lv) was increased in the cerebellar granular layer, the caudate nucleus, the globus pallidus, the substantia nigra, the superior colliculus, and the dentate gyrus. There was a selective increase of Lv in the hippocampus (CA1 strata pyramidale and lacunosum and CA3 strata pyramidale and oriens) and in somatosensory cortex layers V and VI, motor cortex layers II, III, V, and VI, and auditory cortex layers II and III. An increase in capillary surface area per unit volume of tissue was also determined in several brain areas, including layer IV of somatosensory cortex, where Lv was not significantly increased. The O2 diffusion conductance and PO2 in the tissues were estimated with a mathematical model. The remodeling of capillary diameter and length during chronic hypoxia accounts for the significant increase of O2 conductance to neural tissues. Also the estimated tissue PO2 in chronic brain hypoxia is markedly increased in the caudate nucleus and the substantia nigra compared with acute hypoxia. These results suggest that formation of new capillaries is an important mechanism to restore the O2 deficit in chronic brain hypoxia and that local rates of energy utilization may influence angiogenesis in different areas of the brain.
whisker barrels; capillary remodeling
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX
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OXYGEN DIFFUSION through brain capillaries is a critical step in the energy metabolism of neurons. PO2 in the blood, the effective vascular surface of gas exchange, and its utilization by the brain are critical parameters involved in this process. When O2 availability is reduced, as in acute mild-to-moderate hypoxia, an increase of blood flow helps restore the overall delivery of O2 to the brain. However, if the hypoxic insult persists, polycythemia and brain angiogenesis develop (7, 11, 12, 22-25, 28), and this suggests that the initial compensatory mechanisms may not be sufficient to sustain a normal PO2. Although several studies have shown that capillary networks were enlarged in chronic hypoxia, capillary length and surface areas have been quantitatively evaluated only in normoxic conditions (2). In addition, regional differences in brain energy metabolism suggest that marked variations in angiogenesis might develop (18). We hypothesized that changes in the capillary length and surface area per unit volume of tissue as well as a reduction of the intercapillary distances (ICD) might also reflect the heterogeneity of energy utilization among different layers and groups of neurons in the brain. The evaluation of these parameters is required to estimate the effectiveness of angiogenesis to restore PO2 in small regions of the brain during chronic hypoxia. To answer these questions, we studied the vascular architecture of young adult mice exposed to chronic hypoxia for 4 wk and determined the changes induced in capillary length, surface area, internal diameters, and ICD of several brain regions. A mathematical model was used to estimate O2 diffusion conductances (Ec) and tissue tensions.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX
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Animals
Seven 21-day-old male Balb/c mice were maintained in a hypobaric chamber at 455 Torr for 28 days, as described previously (4, 30). The animals remained in the chamber for 23 h/day; they descended to sea level for 1 h for cleaning and feeding. Littermate controls (n = 7) were housed at sea level outside the chamber in similar conditions (755 Torr). Food and water were provided ad libitum, and temperature was maintained at 20°C.Tissue Processing
After 4 wk, control and experimental animals were deeply anesthetized with pentobarbital sodium (40 mg/kg ip) and perfused through the heart with use of a Masterflex pump at 1 ml/min, first with saline heparin (1 U/ml)-1 mM EDTA for 10 min, then with PLP (0.01 M sodium m-periodate, 0.075 M lysine, 2% paraformaldehyde, 0.073 M sodium phosphate) for 10 min, and finally with Kodak NTB 2 photographic emulsion (International Biotechnologies, New Haven, CT) (6) for 10 min. All the solutions were kept at 37°C during perfusion. The brains were carefully removed, placed in cold PLP-30% sucrose to sink, and stored at 4°C until processed. Serial coronal frozen sections were cut at 50 µm, mounted on chrome-alum-subbed slides, developed photographically to visualize the emulsion-filled vessels (5), stained with 1% thionin, dehydrated, cleared in xylol, and coverslipped.Image Analysis
Images of the capillaries were obtained by video microscopy (37) and digitized with a capture card (Scion, Frederick, MD) in a Macintosh IIx computer (Apple, Cupertino, CA). The software Image 1.31 (developed by Dr. Wayne Rasband, National Institutes of Health, Bethesda, MD) was used to obtain measurements of the capillary length per unit volume of tissue (Lv), diameters, and the projected areas of the capillary plexuses. These measurements were performed in regions containing capillaries completely filled with the emulsion. The length of all the capillaries and their diameters within a selected area were drawn by hand on the computer screen, and the length was calculated by converting the pixels to micrometers according to calibrated scales that were digitized in the same way as the vessels. To have a precise anatomic localization of the layers and to avoid measuring small venules and arterioles, a ×40 (0.5 NA) lens was used, and capillaries were defined as having an internal diameter <7 µm as a size criterion (29).Parameters Measured and Calculated
Lv (mm/mm3), capillary surface area (Sv, mm2/mm3), and ICD (µm) were used to determine the capillary density. Capillary diameters were averaged for each brain region from 40 measurements perpendicular to the longitudinal axis of the vessels. Lv was calculated from the total projected length of capillaries (
L'i) within the volume of the sections [volume = section
thickness (T) × area
(A)] by the equation
Lv = 
L'i/
TA (29). Because Lv
varies greatly between adjacent layers in the cortex and other brain
nuclei, we limited our measurements of Lv within the
anatomic boundaries of these regions. The correction factor 4/
assumes random orientation of capillaries in the tissue. Sv was estimated
from the projected areas of capillaries
(
A'i
was measured in pixels by using a threshold that filled all the
capillaries with the program Image 1.31. Sv was calculated
as follows: Sv = A'i/TA
(29). To evaluate changes in the ICD, the diameter of the Krogh
cylinder (2R) can be used as an
estimation of this parameter. R, the
Krogh radius, was estimated as follows: R = 1/
.
Model
A model to estimate Ec using morphological parameters was derived. In this particular study, Ec is estimated from the measurements of Lv and capillary radius (r) with a modified version of Sharan et al. (32) that gives Ec per unit volume of neural tissue (Vti). It is also assumed that the tissue consists of homogeneous cylindrical compartments that surround capillaries that are involved in the exchange process. The utilization of O2 by the tissues (M) is considered to be homogeneous within the cylinder. In this study we assume a value of M for brain metabolism of 0.8 × 10
3 ml
O2 · g1 · s1
(32). Although PO2 is likely to be
heterogeneous along the capillaries, in this study we consider the
capillary pressure similar to the end-capillary pressure. For
derivation of equations for
Ec and tissue
PO2
(PtiO2) see the
APPENDIX.
Statistics
Indexes of capillary density, the internal diameters, and diffusion conductances were compared for different brain regions between the chronic hypoxic and control groups by use of the Student's independent t-test, and differences were accepted as significant when P < 0.05.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX
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Similar to previous studies, hypoxic mice had lower body and brain weights. However, although the hypoxic brains were grossly similar to controls, after tissue processing all the hypoxic animals showed an increase of 25% of cortical volume compared with controls. The striatum, thalamus, and mesencephalic nuclei as well as the cerebellum did not show a change in volume.
Histology
Capillaries in different brain regions of chronic hypoxic and control animals were filled with photographic emulsion. The cerebral and cerebellar cortices as well as the deeper nuclei of hypoxic mice showed altered capillary networks. The cerebellar folia of hypoxic mice showed a dramatic increase in the number of capillaries in the granular layer (Fig. 1, A and B). Compared with controls, hypoxic capillaries appeared elongated and more tortuous and dilated. Changes similar to those observed in the granular layer were also evident in the corpus striatum and thalamic and mesencephalic nuclei. The increase in capillary length was associated with a reduction of the ICD, as shown for capillaries of the substantia nigra (Fig. 1, C and D). The capillary plexuses in the hippocampal formation were also remodeled with chronic hypoxia. As shown in Fig. 2, elongated capillaries were visualized in most layers of areas CA1 and CA3 and the dentate gyrus.
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All the layers of motor cortex showed enlarged capillaries in chronic
hypoxia (Fig. 3). These capillaries were
more tortuous and dilated than those of the control group. Capillaries
in the somatosensory cortex of hypoxic mice were denser, with
larger diameters (Fig. 4).
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Morphometry
Lv and ICD.
Capillary lengths and the estimated ICDs are shown in Table
1 and were consistent with histological
changes in chronic hypoxia. In the hypoxic group the granular layer of
the cerebellum had the greatest absolute increase in
Lv, but
Lv did not
increase in the molecular layer. Other regions with significantly
increased Lv were
the superior colliculus (1.67-fold), substantia nigra (1.66-fold),
caudate nucleus (1.63-fold), globus pallidus (1.32-fold), and subiculum
(1.58-fold). In the hippocampus, longer capillaries were detected in
CA1 strata pyramidale (1.33-fold) and lacunosum (1.54-fold), CA3 strata
oriens (1.47-fold) and pyramidale (1.28-fold), and dentate gyrus strata
moleculare (1.34-fold) and granulosum (1.23-fold).
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Sv and internal diameters.
To examine the contribution of other variables to capillary remodeling
in chronic hypoxia,
Sv and the
average capillary diameter (D) were
measured in selected nuclei and areas of the hippocampus and neocortex.
Sv from digitized
images are shown in Table 2. In the regions
and layers studied in the hypoxic animals,
Sv increased 1.21- to 3.03-fold compared with the control group.
Layers II, III, and IV of the somatosensory cortex, which did not show
a significant increase in
Lv after chronic
hypoxia, still increased the total surface of the capillary bed (Fig.
5).
Sv also increased in all other layers in the somatosensory and motor cortices as well as
nuclei of the basal ganglia, cerebellum, and
hippocampus.
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Ec and
PtiO2.
Ec estimates in
different brain regions and layers of the neocortex and hippocampus are
presented in Fig. 6. Except for
somatosensory layers II and III, a marked increase of
Ec is observed in
all areas studied in the hypoxic group compared with the controls. Ec is a function
of capillary Lv
and diameter. In layer IV of the somatosensory cortex, the increase in
Ec is explained
only by capillary dilation. In contrast, the modest increase in several layers of CA1 and CA3 is only secondary to an increase in
Lv.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX
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The balance between the energy requirements and the effective capillary surface area of a brain region is poorly understood. In conditions of normal PO2, different brain regions have shown a remarkable plasticity to adapt to a local change of energy demands. Regions with high neuronal activity such as layers IV and V of the somatosensory cortex (barrel field) (40) contain capillary networks with a high density of microvessels and shorter ICD. Our results confirm and extend previous studies (7, 11, 12, 22-25, 28) showing an increase of capillary networks in the brain of rodents exposed to chronic hypoxia.
We have measured several morphometric parameters (Lv, Sv, and ICD). Our data show a remarkable range of Lv among different cortical layers in normoxic and chronic hypoxic mice, probably reflecting the different metabolic activities of their neurons. In this regard, somatosensory layer IV neurons, which are very active and contain high levels of cytochrome c oxidase activity (15, 39), are surrounded by densely packed capillary networks. Although we expected that in chronic hypoxia all the different cortical layers would increase Lv proportionally, our findings showed a different response. In the case of the motor cortex, all layers increased their Lv, but in the somatosensory cortex only layers V and VI significantly increased Lv. On the other side, only layers II and III of the auditory cortex increased Lv, whereas changes were not detectable in the visual cortex. We do not know the mechanisms by which the density of capillaries within a small region of the brain are determined, but if we assume the local consumption of O2 to be the principal determinant of Lv, it follows that different Lv increases between adjacent layers of neurons in the cortex may reflect different levels of metabolic adaptation to chronic hypoxia. Outside the cortex and the cerebellum, other regions studied showed less increase in vascularization.
An enlargement of cortical volume in chronic hypoxic animals after tissue processing was a common finding in several groups of mice. This effect of tissue processing is rather perplexing, especially when the finding of a modest decrease of brain weight in adult rodents after prolonged exposure to hypobaric hypoxia is taken into account. Although we do not have an explanation, an increased cortical volume in chronic hypoxic mice does not invalidate the differences found in Lv, but it suggests that, in vivo, the Lv of these capillaries must be higher. However, it remains to be determined whether cortical expansion is secondary to the mechanical effect of an increased number of capillaries filled with the autoradiography emulsion or whether other properties of the tissue are changed in chronic hypoxia.
A question that must be addressed is whether these capillaries represent new vessels or opening of preexisting ones. With use of a double-staining technique (10), it has been shown that perfused and morphologically existing capillary networks in different brain regions of awake normocapnic rats are the same. Also an elevation of brain blood flow secondary to hypercapnia is not associated with capillary recruitment (9), and the increase in blood flow of several brain areas in acute hypoxia is mediated by an increase of flow velocity and microvessel dilation (3). Additional evidence of brain angiogenesis induced by chronic hypobaric hypoxia was recently demonstrated in rats (12), in which early hypertrophy of brain microvessels was followed by hyperplasia. These data are consistent with the concept that reserve capillaries are absent in the brain and that the vessels measured contain a subpopulation of capillaries induced by hypoxia.
Dilation of brain capillaries is another marker of capillary remodeling in the brains of chronic hypoxic mice. This effect of chronic hypoxia was initially described in adult rats by Mercker and Schneider (23), and it is not restricted to areas where Lv was increased but also was prominent in somatosensory layer IV, an area in which Lv did not change. Capillary dilation by itself is a potential mechanism to increase blood flow. In the setting of chronic hypoxia and blood hyperviscosity, capillary dilation would not only help accommodate the increased blood flow but also reduce the resistance due to hyperviscosity (17). According to Poiseuille's law, the flow of a fluid in a vessel decreases linearly with an increase of its viscosity, but it increases as the fourth power of its internal radius. In this regard, it has been determined that the optimal cardiovascular response to chronic hypoxia requires a hematocrit close to normal values (34, 38) and that the development of polycythemia and hyperviscosity as part of the acclimatization to high altitude in humans and other mammals may be detrimental for blood flow (26, 27).
The initial adaptive response to acute hypoxia is an increase of the respiratory rate and a preferential redistribution of blood flow to the brain and heart (8, 14). In acute hypoxia, blood flow increases in various brain regions (35), but as hyperventilation persists, a reduced arterial CO2 blunts the initial increase in blood flow (31, 33) and the vasodilatory response of cerebral arterioles is partially attenuated. In chronic hypoxia, total capillary volume is increased, and, as a result, an elevation of brain blood flow could also be expected. However, in humans native to high altitude (Puno, Peru, 4,000 m) a reduction of blood flow has been shown in several brain areas (16). The higher prevalence of migraine and polycythemia in human populations of the high altitudes (1) suggests that other disturbances of vascular autoregulatory mechanisms in the brain may influence capillary blood flow. It is possible that brain capillary dilation in chronic hypoxia is an adaptive mechanism that begins in the initial steps of the hypoxic insult and persists as polycythemia develops. In this setting, dynamic changes in local blood flow that would accompany a transitory increase in tissue metabolism must be critical to sustain an appropriate PtiO2 proportionate to O2 consumption. Also, it is possible that a failure of the autoregulatory properties of the cerebral vasculature may contribute to the pathophysiology of migraine in natives of high altitudes.
It is important to consider how the rearrangement of capillary plexuses in the brain might affect O2 diffusion and its partial pressure in the tissues, but both variables are difficult to measure directly in the brain. Tenney and Ou (36) predicted increased O2 diffusion into tissues on the basis of the diffusion of CO from subcutaneous pockets implanted in chronic hypoxic rats. Our estimates of Ec for different brain regions also show that an increased diffusion of O2 is expected secondary to the increased Sv in chronic hypoxia. However, the modest increase of Ec in several layers of the hippocampus suggests that this area must be at a particularly higher risk of chronic hypoxia.
The morphological changes described account for an increased Ec in chronic hypoxia, but the gradient of O2 diffusion is also dependent on capillary PO2 and PtiO2. When PtiO2 is estimated using Eq. 2 (Fig. 7), even with an elevated Ec (increases in Lv and r), the effective pressure of O2 in the tissues is limited by the venous PO2. Nevertheless, changes in microvasculature lead to an average increase in PtiO2 of 3 Torr compared with acute hypoxia. Moreover, the estimates of PtiO2 depicted in Fig. 7 suggest that, depending on the initial position on the PtiO2-Lv curve, some brain regions may show greater increases in O2 as a result of increasing Lv than do others. For example, the increase in Ec in the caudate nucleus and substantia nigra, two areas with initially low Lv, accounts for a greater increase in PtiO2 than in the cerebellar granular layer, in which Lv also increases substantially (7.92 and 1.65 Torr in the caudate nucleus and cerebellar granule cell layer, respectively). In contrast, in somatosensory layer IV, a region in which hypoxia does not induce the formation of new capillaries, there is only a small increase in PtiO2 (1.25 Torr) related to diameter increases. This suggests than in normal conditions some well-vascularized areas of the brain already have a maximal density of capillaries that is not changed by the hypoxic stimulus. More studies are needed to determine the nature of the factors that may limit angiogenesis in chronic hypoxia.
The persistence of brain hypoxia, despite the development of polycythemia and the remodeling of capillary plexuses, leads one to look outside these parameters for other adaptive mechanisms. According to Kety's equation for Krogh's model (19), an additional increase in PtiO2 is predicted when M decreases. In this regard, metabolically intact mitochondria isolated from the cerebral cortex of chronic hypoxic mice showed a decreased O2 consumption in the presence of ADP (state 3 of respiration) compared with mitochondria from normoxic controls (4). Also the activities of complex INADH dehydrogenase and cytochrome c oxidase of the respiratory chain are decreased in the brain after exposure to prolonged environmental hypoxia (4, 21), showing that a reduced expression of these enzymes contributes to the decrease in O2 consumption by brain mitochondria. The increase in the metabolic rate for glucose (13) and the density of glucose transporter in isolated microvessels of rats exposed to hypobaric hypoxia (11) suggest that brain energy metabolism in chronic hypoxia is more dependent on anaerobic glycolysis. A possible effect of reduced brain mitochondrial O2 consumption in chronic hypoxia would be an increase in PtiO2 values closer to the levels calculated for normoxic conditions. Thus it is possible that a reduction of O2 utilization coupled with increased O2 diffusion secondary to angiogenesis may help restore PtiO2 and adapt the brain to low blood PO2. However, more accurate determinations of local O2 utilization are needed to compare energy metabolism and capillary architecture in the brain.
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APPENDIX |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX
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To estimate the mean PtiO2, we derived an equation from the Krogh-Erlang formula modified by Kety (19, 20)
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(1) |
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(2) |
5
cm2/s) and
ti is the
O2 solubility in the tissue (3 × 105
ml · ml1 · Torr1).
R is the radius of the Krogh's
cylinder, and r is the capillary radius. PcO2 is
taken as the end-capillary PO2 with
values of 40 Torr at sea level and 30 Torr in the chronic hypoxic
group; these values are similar to those estimated in chronic hypoxic rats by Tenney and Ou (36). M is the
O2 consumption per unit volume of
Krogh cylinder (not including the intracapillary volume). It is
important to note that the Krogh-Erlang equation is based on the
assumption that O2 diffusion is
adequate to supply the metabolic need of
O2 throughout the cylinder.
We slightly modify the model of Sharan et al. (32) by taking quantities per unit neural tissue volume instead of per whole brain. The amount of O2 delivered from the capillary compartment per unit volume of Krogh cylinder (Jc) is
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(3) |
PtiO2) is the
average PO2 differential between the
capillary and the tissue. In addition,
Jc can be
expressed as
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(4) |
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(5) |
1 · ml1 · Torr1.
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ACKNOWLEDGEMENTS |
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We are grateful to Dr. Carlos Monge for advice during the preparation of the manuscript, Manuel Panta for excellent technical support, and Kathryn Diekmann for help in the preparation of the manuscript.
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FOOTNOTES |
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This study was supported by National Institute of Neurological Disorders and Stroke Grants NS-17763 and NS-28781, the McDonnell Center for Studies of Higher Brain Function, an award from the Spastic Paralysis Foundation of the Illinois-Eastern Iowa District of the Kiwanis International, and Consejo Nacional de Ciencia y Tecnologia (Lima, Peru).
Address for reprint requests: T. A. Woolsey, Dept. of Neurological Surgery, Campus Box 8057, Washington University School of Medicine, St. Louis, MO 63110 (E-mail: woolseyt{at}medicine.wustl.edu).
Received 24 December 1997; accepted in final form 18 November 1998.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
APPENDIX
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, Control
(PvO2 = 40 Torr); 
, "hypoxia"
without microvascular changes (PvO2 = 30 Torr); 
, chronic hypoxia with microvascular changes
(PvO2 = 30 Torr). Arrows,
increase in
PtiO2 secondary
to microvascular changes in selected areas of mouse brain. In chronic
hypoxia, PtiO2
values increased more in caudate nucleus and substantia nigra than in
other areas of brain [cerebellum and somatosensory (SS) layer
IV].