HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 295/3/R864    most recent 00536.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Schmid-Brunclik, N. Articles by Ogunshola, O. O. Search for Related Content PubMed PubMed Citation Articles by Schmid-Brunclik, N. Articles by Ogunshola, O. O.

NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Astrocyte responses to injury: VEGF simultaneously modulates cell death and proliferation

Institute of Veterinary Physiology, Vetsuisse Faculty and Zürich Centre for Integrative Human Physiology, University of Zürich, Zürich, Switzerland

Submitted 26 July 2007 ; accepted in final form 23 June 2008

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-1 (HIF-1) induction plays a role in tolerance of these cells to insult. Thus primary astrocytes were subjected to normoxic (21% O₂), hypoxic (1% O₂), or near-anoxic (<0.1% O₂) 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-1 protein and provoked DNA binding activity, whereas oxygen and glucose deprivation accelerated HIF-1 accumulation. Unexpectedly, Hif-1 knockdown studies showed that elevated VEGF levels following increased insult was only partially due to HIF-1 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.

oxygen deprivation; glucose withdrawal; blood-brain barrier; glial scarring