Normobaric Hypoxia Induces Tolerance to Focal Permanent Cerebral Ischemia in Association with an Increased Expression of Hypoxia-Inducible Factor-1 and its Target Genes, Erythropoietin and VEGF, in the Adult Mouse Brain

Abstract

Summary:Tolerance to cerebral ischemia is achieved by preconditioning sublethal stresses, such as ischemia or hypoxia, paradigms in which the decrease of O 2 availability may constitute an early signal inducing tolerance. In accordance with this concept, this study shows that hypoxia induces tolerance against focal permanent ischemia in adult mice. Normobaric hypoxia (8% O 2 of 1-hour, 3-hour, or 6-hour duration), performed 24 hours before ischemia, reduces infarct volume by approximately 30% when compared with controls. To elucidate the mechanisms underlying this neuroprotection, the authors investigated the effects of preconditioning on cerebral expression of hypoxia-inducible factor-1␣ (HIF-1␣) and its target genes, erythropoietin and vascular endothelial growth factor (VEGF). Hypoxia, whatever its duration (1 hour, 3 hours, 6 hours), rapidly increases the nuclear content of HIF-1␣ as well as the mRNA levels of erythropoietin and VEGF. Furthermore, erythropoietin and VEGF are upregulated at the protein level 24 hours after 6 hours of hypoxia. The authors' findings show that (1) hypoxia elicits a delayed, short-lasting (<72 hours) tolerance to focal permanent ischemia in the adult mouse brain; (2) HIF-1 target genes could contribute to the establishment of tolerance; and (3) this model might be a useful paradigm to further study the mechanisms of ischemic tolerance, to identify new therapeutic targets for stroke.

Maternal Undernutrition Induces the Expression of Hypoxia-Related Genes in the Fetal Brain

“…3d). The accumulation of HIF1α protein induces tolerance to hypoxia in the adult brain (Bernaudin et al 2002). It is therefore conceivable that maternal undernutrition may change the tolerance to hypoxia in OPCs by accumulating HIF1α.…”

Targeting Astrocytes for Stroke Therapy

“…110 In rats, hypoxic preconditioning was mirrored by an increase in VEGF levels in astrocytes. 111 It should be noted, however, that astrocytes are not the sole source of VEGF in the brain. In fact, both microglia and neurons contribute to VEGF abundance after hypoxia.…”

Involvement of circulating endothelial progenitor cells and vasculogenic factors in the pathogenesis of diabetic retinopathy

“…9,16,17 Sublethal hypoxia induces upregulation and nuclear translocation of hypoxia-inducible factor, whose target gene is Epo. [18][19][20][21] Epo stimulates postnatal neovascularization at least in part by enhancing mobilization of EPCs from the bone marrow. 22,23 Epo is also known to enhance mobilization of EPCs from bone marrow and maintain normal endothelial differentiation of retina on ischemic tissue to help the wound healing process.…”