Vascular endothelial growth factor mediates vasogenic edema in acute lead encephalopathy

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.