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First published online August 6, 2004
Journal of Experimental Biology 207, 3163-3169 (2004)
Published by The Company of Biologists 2004
doi: 10.1242/jeb.00976

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Structural and functional adaptation to hypoxia in the rat brain

Joseph C. LaManna^*, Juan Carlos Chavez and Paola Pichiule

Departments of Neurology and Anatomy, Case Medical School, Cleveland, OH 44106, USA

View larger version (16K): [in a new window]   Fig. 1. Ventilation rate of rats (means ± S.D.) placed in a plethysmograph (Buxco, Inc., Wilmington, NC, USA) after various periods of exposure to 10% oxygen (balance nitrogen). N=3 rats per group (LaManna et al., unpublished observations).

View larger version (21K): [in a new window]   Fig. 2. Mean day (lower) and night time (upper) body temperature changes, recorded through an implantable sensor and transmitter system (Mini Mitter, Co. Inc., Bend, OR, USA), in a single rat exposed to hypobaric hypoxia initiated at Day 0. For each daily cycle, the higher temperature is recorded during the dark, behavioral active phase (night). After an initial drop and loss of diurnal rhythm, there is a recovery within 1 week and then a secondary minor down trend of about 0.015°C day–1 (LaManna et al., unpublished observations).

View larger version (20K): [in a new window]   Fig. 3. (A) Histogram of O2 partial pressure in rat cerebral cortex (PtO2) obtained by making multiple cortical penetrations (in 100 µm steps) with an O2-sensitive platinum microelectrode during normoxia. The histogram was constructed from 136 measurements taken from 13 rats. (B) Histogram of PtO2 taken from telencelphalon of the freshwater diving turtle (P. scripta). Histogram constructed from 71 samples from 11 turtles. The class interval in both A and B is 1 torr. Reprinted by permission from Sick et al. (1982).

View larger version (55K): [in a new window]   Fig. 4. Changes in cortical capillary density during prolonged hypoxia and deadaptation. (A) Composite photomicrograph of GLUT-1-stained sections spanning part of the parietal cortex at normoxia, 21 days (21 d) of hypoxia, and normoxic recovery for 21 days. (B) Capillary density analysis of GLUT-1-stained sections showing a significant increase at 21 days of hypoxia (21 d H). Subsequent normoxic recovery (7 d R, 14 d R, or 21 d R) caused reestablishment of prehypoxic capillary density. Values are means ± S.D.; N=4 rats in each group. *P<0.05 compared with controls (C). Reprinted with permission from Pichiule and LaManna (2002).

View larger version (45K): [in a new window]   Fig. 5. This scheme represents the current concept for hypoxia-inducible factor-1 (HIF-1) pathways. In normoxic conditions, HIF-1 is continuously produced and, in the presence of Fe2+ and oxygen, is continuously degraded through the Von Hippel Lindau protein (VHL)/Ubiquitin/Proteosome pathway. When oxygen becomes limiting, prolyl hydroxylase is inhibited and HIF-1 accumulates. After translocation and combination with the constitutive HIF-1, the transcription factor binds to hypoxic response element (HRE) sequences to upregulate a number of downstream genes such as erythropoietin (EPO), VEGF, lactate dehydrogenase (LDH), inducible nitric oxide synthase (iNOS), GLUT-1 and enolase-1 (ENO). (Drawing by Max Neal.)

View larger version (54K): [in a new window]   Fig. 6. (A) The glucose transporter at the blood–brain barrier, GLUT-1, is upregulated in rat brain in response to hypobaric hypoxia from 6 h (6h) to 21 days (21d), reaching a maximum between 1 and 2 weeks. After return to normoxia over 3 weeks (1R – 21R) there is a return towards control levels of the GLUT-1 protein. (B) Immunohistochemistry of serial sections from rat cerebellar cortex suggesting that VEGF is upregulated in cells that are also positive for the astrocyte specific marker glial fibrillary acific protein (GFAP), rather than the capillary endothelial cells that are positive for the glucose transporter (GLUT-1) (LaManna et al., unpublished observations).

View larger version (23K): [in a new window]   Fig. 7. Scheme of the proposed relationship between VEGF and Ang-2 in controlling capillary density. The constitutive Ang-1, produced in pericytes and neighboring cells, normally maintains mechanical stability of the capillary through interaction with the Tie-2 receptor. Upregulated Ang-2, occurring during changes in oxygen availability, binds to the Tie-2 receptor without phosphorylation/activation, blocking Ang-1, releasing the pericyte and destabilizing the capillary. During hypoxic exposure, in the presence of VEGF, there is endothelial cell proliferation and angiogenesis. But, during reoxygenation after hypoxic adaptation in the absence of VEGF there is apoptosis and vessel regression. (Drawn by P. Pichiule, based on the hypothesis presented by Holash et al., 1999.)

View larger version (52K): [in a new window]   Fig. 8. HIF-1 accumulates in vivo in response to both hypoxic hypoxia and cobalt chloride, administered intraperitoneally, in the 6 month rat brain cortex. At 24 months, however, there is greatly diminished accumulation of HIF-1 under hypoxic conditions, but the response to cobalt chloride is still robust. ß-actin was used as a loading control (Chavez and LaManna, 2003).

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