Vascular endothelial growth factor mediates vasogenic edema in acute lead encephalopathy

Authors:
  • JRJuliet C. Russell
    Juliet C. Russell
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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. Pb2+ 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.

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