| Astrocyte responses to injury: VEGF simultaneously modulates cell death and proliferation. | |
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MedLine Citation:
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PMID: 18614764 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hypoxia is linked to changes in blood-brain barrier (BBB) permeability, and loss of BBB integrity is characteristic of many pathological brain diseases including stroke. In particular, astrocytes play a central role in brain homeostasis and BBB function. We investigated how hypoxia affects astrocyte survival and assessed whether VEGF release through hypoxia-inducible factor-1alpha (HIF-1alpha) induction plays a role in tolerance of these cells to insult. Thus primary astrocytes were subjected to normoxic (21% O(2)), hypoxic (1% O(2)), or near-anoxic (<0.1% O(2)) conditions in the presence or absence of glucose. Cell death was significantly initiated after combined oxygen glucose deprivation, and, surprisingly, astrocyte proliferation increased concomitantly. Near anoxic, but not hypoxic, conditions stabilized HIF-1alpha protein and provoked DNA binding activity, whereas oxygen and glucose deprivation accelerated HIF-1alpha accumulation. Unexpectedly, Hif-1alpha knockdown studies showed that elevated VEGF levels following increased insult was only partially due to HIF-1alpha induction, suggesting alternative mechanisms of VEGF regulation. Notably, endogenous VEGF signaling during insult was essential for cell fate since VEGF inhibition appreciably augmented cell death and reduced proliferation. These data suggest Hif-1 only partially contributes to VEGF-mediated astrocyte responses during chronic injury (as occurs in clinical hypoxic/ischemic insults) that may ultimately be responsible for disrupting BBB integrity. |
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Authors:
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Nicole Schmid-Brunclik; Carole Bürgi-Taboada; Xanthi Antoniou; Max Gassmann; Omolara O Ogunshola |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-07-09 |
Journal Detail:
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Title: American journal of physiology. Regulatory, integrative and comparative physiology Volume: 295 ISSN: 0363-6119 ISO Abbreviation: Am. J. Physiol. Regul. Integr. Comp. Physiol. Publication Date: 2008 Sep |
Date Detail:
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Created Date: 2008-09-08 Completed Date: 2008-10-17 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100901230 Medline TA: Am J Physiol Regul Integr Comp Physiol Country: United States |
Other Details:
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Languages: eng Pagination: R864-73 Citation Subset: IM |
Affiliation:
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Institute of Veterinary Physiology, Vetsuisse Faculty, Univ. of Zurich, Winterthurerstrasse 260, Zurich CH 8057, Switzerland. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Astrocytes / cytology*, metabolism*, secretion Blood-Brain Barrier / physiology Brain Ischemia / metabolism, pathology* Cell Death / drug effects, physiology* Cell Division / drug effects, physiology Cell Hypoxia / physiology Cell Survival / drug effects, physiology Cells, Cultured Glucose / pharmacology Hypoxia-Inducible Factor 1, alpha Subunit / genetics, metabolism Oxygen / pharmacology RNA, Small Interfering Rats Rats, Wistar Vascular Endothelial Growth Factor A / metabolism*, secretion |
| Chemical | |
Reg. No./Substance:
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0/Hif1a protein, rat; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/RNA, Small Interfering; 0/Vascular Endothelial Growth Factor A; 0/vascular endothelial growth factor A, rat; 50-99-7/Glucose; 7782-44-7/Oxygen |
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