Abstract
Brain injury from inorganic Pb^2+^ is considered the most important environmental childhood health hazard worldwide. The microvasculature of the developing brain is uniquely susceptible to high level Pb^2+^ toxicity (ie, Pb^2+^ encephalopathy) characterized by cerebellar hemorrhage, increased bloodβbrain barrier permeability, and vasogenic edema. However, the specific molecular mediators of Pb^2+^ encephalopathy have been elusive. We found that Pb^2+^ induces vascular endothelial growth factor/vascular permeability factor (VEGF) in cultured astrocytes (J Biol Chem, 2000;275:27874β27882). The study presented here asks if VEGF dysregulation contributes mechanistically to Pb^2+^ encephalopathy. Neonatal rats exposed to 4% Pbβcarbonate develop the histopathological features of Pb^2+^ 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 Pb^2+^ intoxication. Pb^2+^ exposure increased phosphorylation of cerebellar Flkβ1 VEGF receptors and the Flkβ1 inhibitor CEPβ3967 completely blocked cerebellar edema formation without affecting microhemorrhage formation or bloodβbrain barrier permeability. This establishes that Pb^2+^βinduced vasogenic edema formation develops via a Flkβ1βdependent mechanism and suggests that the vascular permeability caused by Pb^2+^ is Flkβ1 independent.