Vascular Endothelial Growth Factor Mediates Vasogenic Edema in Acute Lead Encephalopathy

Mir Ahamed Hossain, Juliet C. Russell, Sheila Miknyoczki, Bruce Ruggeri, Bachchu Lal, John Laterra

Research output: Contribution to journalArticlepeer-review


Brain injury from inorganic Pb2+ is considered the most important environmental childhood health hazard worldwide. The microvasculature of the developing brain is uniquely susceptible to high level Pb2+ toxicity (ie, Pb2+ encephalopathy) characterized by cerebellar hemorrhage, increased blood-brain barrier permeability, and vasogenic edema. However, the specific molecular mediators of Pb2+ encephalopathy have been elusive. We found that Pb2+ induces vascular endothelial growth factor/vascular permeability factor (VEGF) in cultured astrocytes (J Biol Chem, 2000;275:27874-27882). The study presented here asks if VEGF dysregulation contributes mechanistically to Pb2+ encephalopathy. Neonatal rats exposed to 4% Pb-carbonate develop the histopathological features of Pb2+ encephalopathy seen in children. Cerebellar VEGF expression increased approximately twofold (p < 0.01) concurrent with the development of cerebellar microvascular hemorrhage, enhanced vascular permeability to serum albumin, and vasogenic cerebellar edema (p < 0.01). No change in VEGF expression occurred in cerebral cortex that does not develop these histopathological complications of acute Pb2+ intoxication. Pb 2+ exposure increased phosphorylation of cerebellar Flk-1 VEGF receptors and the Flk-1 inhibitor CEP-3967 completely blocked cerebellar edema formation without affecting microhemorrhage formation or blood-brain barrier permeability. This establishes that Pb2+-induced vasogenic edema formation develops via a Flk-1-dependent mechanism and suggests that the vascular permeability caused by Pb2+ is Flk-1 independent.

Original languageEnglish (US)
Pages (from-to)660-667
Number of pages8
JournalAnnals of neurology
Issue number5
StatePublished - May 2004

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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