Cerebral adaptations to chronic anemia in a model of erythropoietin- deficient mice exposed to hypoxia

Raja El Hasnaoui-Saadani, Aurélien Pichon, Dominique Marchant, Paul Olivier, Thierry Launay, Patricia Quidu, Michèle Beaudry, Alain Duvallet, Jean Paul Richalet, Fabrice Favret

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Abstract

Anemia and hypoxia in rats result in an increase in factors potentially involved in cerebral angiogenesis. Therefore, the aim of this study was to assess the effect of chronic anemia and/or chronic hypoxia on cerebral cellular responses and angiogenesis in wild-type and anemic transgenic mice. These studies were done in erythropoietin-deficient mice (Epo-TAgh) in normoxia and following acute (one day) and chronic (14 days, barometric pressure = 420 mmHg) hypoxia. In normoxia, Epo-TAgh mice showed an increase in transcript and protein levels of hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), erythropoietin receptors (EpoR), phospho-STAT-5/STAT-5 ratio, and neuronal neuronal nitric oxide synthase (nNOS) along with a higher cerebral capillary density. In wild-type (WT) mice, acute hypoxia increased all of the studied factors, while in chronic hypoxia, HIF-1α, EpoR, phospho-STAT-5/STAT-5 ratio, nNOS, and inducible NOS remained elevated, with an increase in capillary density. Surprisingly, in Epo-TAgh mice, chronic hypoxia did not further increase any factor except the nitric oxide metabolites, while HIF-1α, EpoR, and phospho-STAT-5/STAT-5 ratio were reduced. Normoxic Epo-TAgh mice developed cerebral angiogenesis through the HIF-1α/VEGF pathway. In acute hypoxia, WT mice up-regulated all of the studied factors, including cerebral NO. Polycythemia and angiogenesis occurred with acclimatization to chronic hypoxia only in WT mice. In Epo-TAgh, the decrease in HIF-1α, VEGF proteins, and phospho-STAT-5 ratio in chronic hypoxia suggest that neuroprotective and angiogenesis pathways are altered.

Original languageEnglish
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume296
Issue number3
DOIs
Publication statusPublished - 1 Mar 2009

Fingerprint

Erythropoietin
Anemia
Hypoxia-Inducible Factor 1
Erythropoietin Receptors
Nitric Oxide Synthase Type I
Vascular Endothelial Growth Factor A
Brain Hypoxia
Polycythemia
Vascular Endothelial Growth Factor Receptor
Hypoxia
Acclimatization
Transgenic Mice
Nitric Oxide
Proteins
Pressure

Keywords

  • Angiogenesis
  • Cerebral cortex
  • Chronic anemia
  • Erythropoietin
  • Hypoxia

Cite this

El Hasnaoui-Saadani, Raja ; Pichon, Aurélien ; Marchant, Dominique ; Olivier, Paul ; Launay, Thierry ; Quidu, Patricia ; Beaudry, Michèle ; Duvallet, Alain ; Richalet, Jean Paul ; Favret, Fabrice. / Cerebral adaptations to chronic anemia in a model of erythropoietin- deficient mice exposed to hypoxia. In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2009 ; Vol. 296, No. 3.
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abstract = "Anemia and hypoxia in rats result in an increase in factors potentially involved in cerebral angiogenesis. Therefore, the aim of this study was to assess the effect of chronic anemia and/or chronic hypoxia on cerebral cellular responses and angiogenesis in wild-type and anemic transgenic mice. These studies were done in erythropoietin-deficient mice (Epo-TAgh) in normoxia and following acute (one day) and chronic (14 days, barometric pressure = 420 mmHg) hypoxia. In normoxia, Epo-TAgh mice showed an increase in transcript and protein levels of hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), erythropoietin receptors (EpoR), phospho-STAT-5/STAT-5 ratio, and neuronal neuronal nitric oxide synthase (nNOS) along with a higher cerebral capillary density. In wild-type (WT) mice, acute hypoxia increased all of the studied factors, while in chronic hypoxia, HIF-1α, EpoR, phospho-STAT-5/STAT-5 ratio, nNOS, and inducible NOS remained elevated, with an increase in capillary density. Surprisingly, in Epo-TAgh mice, chronic hypoxia did not further increase any factor except the nitric oxide metabolites, while HIF-1α, EpoR, and phospho-STAT-5/STAT-5 ratio were reduced. Normoxic Epo-TAgh mice developed cerebral angiogenesis through the HIF-1α/VEGF pathway. In acute hypoxia, WT mice up-regulated all of the studied factors, including cerebral NO. Polycythemia and angiogenesis occurred with acclimatization to chronic hypoxia only in WT mice. In Epo-TAgh, the decrease in HIF-1α, VEGF proteins, and phospho-STAT-5 ratio in chronic hypoxia suggest that neuroprotective and angiogenesis pathways are altered.",
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Cerebral adaptations to chronic anemia in a model of erythropoietin- deficient mice exposed to hypoxia. / El Hasnaoui-Saadani, Raja; Pichon, Aurélien; Marchant, Dominique; Olivier, Paul; Launay, Thierry; Quidu, Patricia; Beaudry, Michèle; Duvallet, Alain; Richalet, Jean Paul; Favret, Fabrice.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 296, No. 3, 01.03.2009.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Cerebral adaptations to chronic anemia in a model of erythropoietin- deficient mice exposed to hypoxia

AU - El Hasnaoui-Saadani, Raja

AU - Pichon, Aurélien

AU - Marchant, Dominique

AU - Olivier, Paul

AU - Launay, Thierry

AU - Quidu, Patricia

AU - Beaudry, Michèle

AU - Duvallet, Alain

AU - Richalet, Jean Paul

AU - Favret, Fabrice

PY - 2009/3/1

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N2 - Anemia and hypoxia in rats result in an increase in factors potentially involved in cerebral angiogenesis. Therefore, the aim of this study was to assess the effect of chronic anemia and/or chronic hypoxia on cerebral cellular responses and angiogenesis in wild-type and anemic transgenic mice. These studies were done in erythropoietin-deficient mice (Epo-TAgh) in normoxia and following acute (one day) and chronic (14 days, barometric pressure = 420 mmHg) hypoxia. In normoxia, Epo-TAgh mice showed an increase in transcript and protein levels of hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), erythropoietin receptors (EpoR), phospho-STAT-5/STAT-5 ratio, and neuronal neuronal nitric oxide synthase (nNOS) along with a higher cerebral capillary density. In wild-type (WT) mice, acute hypoxia increased all of the studied factors, while in chronic hypoxia, HIF-1α, EpoR, phospho-STAT-5/STAT-5 ratio, nNOS, and inducible NOS remained elevated, with an increase in capillary density. Surprisingly, in Epo-TAgh mice, chronic hypoxia did not further increase any factor except the nitric oxide metabolites, while HIF-1α, EpoR, and phospho-STAT-5/STAT-5 ratio were reduced. Normoxic Epo-TAgh mice developed cerebral angiogenesis through the HIF-1α/VEGF pathway. In acute hypoxia, WT mice up-regulated all of the studied factors, including cerebral NO. Polycythemia and angiogenesis occurred with acclimatization to chronic hypoxia only in WT mice. In Epo-TAgh, the decrease in HIF-1α, VEGF proteins, and phospho-STAT-5 ratio in chronic hypoxia suggest that neuroprotective and angiogenesis pathways are altered.

AB - Anemia and hypoxia in rats result in an increase in factors potentially involved in cerebral angiogenesis. Therefore, the aim of this study was to assess the effect of chronic anemia and/or chronic hypoxia on cerebral cellular responses and angiogenesis in wild-type and anemic transgenic mice. These studies were done in erythropoietin-deficient mice (Epo-TAgh) in normoxia and following acute (one day) and chronic (14 days, barometric pressure = 420 mmHg) hypoxia. In normoxia, Epo-TAgh mice showed an increase in transcript and protein levels of hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), erythropoietin receptors (EpoR), phospho-STAT-5/STAT-5 ratio, and neuronal neuronal nitric oxide synthase (nNOS) along with a higher cerebral capillary density. In wild-type (WT) mice, acute hypoxia increased all of the studied factors, while in chronic hypoxia, HIF-1α, EpoR, phospho-STAT-5/STAT-5 ratio, nNOS, and inducible NOS remained elevated, with an increase in capillary density. Surprisingly, in Epo-TAgh mice, chronic hypoxia did not further increase any factor except the nitric oxide metabolites, while HIF-1α, EpoR, and phospho-STAT-5/STAT-5 ratio were reduced. Normoxic Epo-TAgh mice developed cerebral angiogenesis through the HIF-1α/VEGF pathway. In acute hypoxia, WT mice up-regulated all of the studied factors, including cerebral NO. Polycythemia and angiogenesis occurred with acclimatization to chronic hypoxia only in WT mice. In Epo-TAgh, the decrease in HIF-1α, VEGF proteins, and phospho-STAT-5 ratio in chronic hypoxia suggest that neuroprotective and angiogenesis pathways are altered.

KW - Angiogenesis

KW - Cerebral cortex

KW - Chronic anemia

KW - Erythropoietin

KW - Hypoxia

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U2 - 10.1152/ajpregu.00119.2008

DO - 10.1152/ajpregu.00119.2008

M3 - Article

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JO - American Journal of Physiology - Regulatory Integrative and Comparative Physiology

JF - American Journal of Physiology - Regulatory Integrative and Comparative Physiology

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