Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates adaptive responses to the lack of oxygen in mammalian cells. HIF-1 consists of two proteins, HIF-1alpha and HIF-1beta. HIF-1alpha accumulates under hypoxic conditions, whereas HIF-1beta is constitutively expressed. HIF-1alpha and HIF-1beta expression were measured during adaptation to hypobaric hypoxia (0.5 atm) in rat cerebral cortex. Western blot analyses indicated that HIF-1alpha rapidly accumulated during the onset of hypoxia and did not fall for 14 days but fell to normal by 21 days despite the continuous low arterial oxygen tension. Immunostaining showed that neurons, astrocytes, ependymal cells, and possibly endothelial cells were the cell types expressing HIF-1alpha. Genes with hypoxia-responsive elements were activated under these conditions, as evidenced by elevated vascular endothelial growth factor and glucose transporter-1 mRNA levels. When 21-day-adapted rats were exposed to a more severe hypoxic challenge (8% oxygen), HIF-1alpha accumulated again. On the basis of these results, we speculate that the vascular remodeling and metabolic changes triggered during prolonged hypoxia are capable of restoring normal tissue oxygen levels.
Rats were exposed to hypobaric hypoxia (0.5 atm) for up to 3 wk. Hypoxic rats failed to gain weight but maintained normal brain water and ion content. Blood hematocrit was increased by 48% to a level of 71% after 3 wk of hypoxia compared with littermate controls. Brain blood flow was increased by an average of 38% in rats exposed to 15 min of 10% normobaric oxygen and by 23% after 3 h but was not different from normobaric normoxic rats after 3 wk of hypoxia. Sucrose space, as a measure of brain plasma volume, was not changed under any hypoxic conditions. The mean brain microvessel density was increased by 76% in the frontopolar cerebral cortex, 46% in the frontal motor cortex, 54% in the frontal sensory cortex, 65% in the parietal motor cortex, 68% in the parietal sensory cortex, 68% in the hippocampal CA1 region, 57% in the hippocampal CA3 region, 26% in the striatum, and 56% in the cerebellum. The results indicate that hypoxia elicits three main responses that affect brain oxygen availability. The acute effect of hypoxia is an increase in regional blood flow, which returns to control levels on continued hypoxic exposure. Longer-term effects of continued moderate hypoxic exposure are erythropoiesis and a decrease in intercapillary distance as a result of angiogenesis. The rise in hematocrit and the increase in microvessel density together increase oxygen availability to the brain to within normal limits, although this does not imply that tissue PO2 is restored to normal.
Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates the adaptive response to hypoxia in mammalian cells. It consists of a regulatory subunit HIF-1␣, which accumulates under hypoxic conditions, and a constitutively expressed subunit HIF-1.In this study we analyzed HIF-1␣ expression in the rat cerebral cortex after transient global ischemia induced by cardiac arrest and resuscitation. Our results showed that HIF-1␣ accumulates as early as 1 hr of recovery and persists for at least 7 d.In addition, the expression of HIF-1 target genes, erythropoietin and Glut-1, were induced at 12 hr to 7d of recovery. A logical explanation for HIF-1␣ accumulation might be that the brain remained hypoxic for prolonged periods after resuscitation. By using the hypoxic marker 2-(2-nitroimidazole-1[H]-y1)-N- (2,2,3,3,3-pentafluoropropyl)-acetamide (EF5), we showed that the brain is hypoxic during the first hours of recovery from cardiac arrest, but the tissue is no longer hypoxic at 2 d. Thus, the initial ischemic episode must have activated other nonhypoxic mechanisms that maintain prolonged HIF-1␣ accumulation. One such mechanism might be initiated by insulin-like growth factor-1 (IGF-1). Our results showed that IGF-1 expression was upregulated after cardiac arrest and resuscitation. In addition, we showed that IGF-1 was able to induce HIF-1␣ in pheochromocytoma cells and cultured neurons as well as in the brain of rats that received intracerebroventricular and systemic IGF-1 infusion. Moreover, infusion of a selective IGF-1 receptor antagonist abrogates HIF-1␣ accumulation after cardiac arrest and resuscitation. Our study suggest that activation of HIF-1 might be part of the mechanism by which IGF-1 promotes cell survival after cerebral ischemia.
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