Vascular Endothelial Growth Factor Mediates Vasogenic Edema in Acute Lead Encephalopathy

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

Research output: Contribution to journalArticle

Abstract

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
Volume55
Issue number5
DOIs
StatePublished - May 2004

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Brain Diseases
Vascular Endothelial Growth Factor A
Edema
Capillary Permeability
Blood-Brain Barrier
Permeability
Hemorrhage
Lead
Vascular Endothelial Growth Factor Receptor
Environmental Health
Carbonates
Microvessels
Serum Albumin
Astrocytes
Cerebral Cortex
Brain Injuries
Phosphorylation
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Vascular Endothelial Growth Factor Mediates Vasogenic Edema in Acute Lead Encephalopathy. / Hossain, Mir Ahamed; Russell, Juliet C.; Miknyoczki, Sheila; Ruggeri, Bruce; Lal, Bachchu; Laterra, John J.

In: Annals of Neurology, Vol. 55, No. 5, 05.2004, p. 660-667.

Research output: Contribution to journalArticle

Hossain, Mir Ahamed ; Russell, Juliet C. ; Miknyoczki, Sheila ; Ruggeri, Bruce ; Lal, Bachchu ; Laterra, John J. / Vascular Endothelial Growth Factor Mediates Vasogenic Edema in Acute Lead Encephalopathy. In: Annals of Neurology. 2004 ; Vol. 55, No. 5. pp. 660-667.
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