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Neural stem/progenitor cells promote endothelial cell morphogenesis and protect endothelial cells against ischemia via HIF-1alpha-regulated VEGF signaling.

Abstract
Vascular cells provide a neural stem/progenitor cell (NSPC) niche that regulates expansion and differentiation of NSPCs within the germinal zones of the embryonic and adult brain under both physiologic and pathologic conditions. Here, we examined the NSPC-endothelial cell (NSPC/EC) interaction under conditions of ischemia, both in vitro and after intracerebral transplantation. In culture, embryonic mouse NSPCs supported capillary morphogenesis and protected ECs from cell death induced by serum starvation or by transient oxygen and glucose deprivation (OGD). Neural stem/progenitor cells constitutively expressed hypoxia-inducible factor 1alpha (HIF-1alpha) transcription factor and vascular endothelial growth factor (VEGF), both of which were increased approximately twofold after the exposure of NSPCs to OGD. The protective effects of NSPCs on ECs under conditions of serum starvation and hypoxia were blocked by pharmacological inhibitors of VEGF signaling, SU1498 and Flt-1-Fc. After intracerebral transplantation, NSPCs continued to express HIF-1alpha and VEGF, and promoted microvascular density after focal ischemia. These studies support a role for NSPCs in stabilization of vasculature during ischemia, mediated via HIF-1alpha-VEGF signaling pathways, and suggest therapeutic application of NSPCs to promote revascularization and repair after brain injury.
AuthorsTamara Roitbak, Lu Li, Lee Anna Cunningham
JournalJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 28 Issue 9 Pg. 1530-42 (Sep 2008) ISSN: 1559-7016 [Electronic] United States
PMID18478024 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Vascular Endothelial Growth Factor A
Topics
  • Animals
  • Embryo, Mammalian
  • Endothelial Cells (physiology)
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit (physiology)
  • Ischemia (etiology)
  • Mice
  • Morphogenesis
  • Neovascularization, Physiologic
  • Neurons (physiology)
  • Signal Transduction
  • Stem Cells (physiology)
  • Vascular Endothelial Growth Factor A (metabolism)

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