Vascular endothelial growth factor mediates vasogenic edema in acute lead encephalopathy

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 blood-brain 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;275:27874-27882). The study presented here asks if VEGF dysregulation contributes mechanistically to Pb(2+) encephalopathy. Neonatal rats exposed to 4% Pb-carbonate 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 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 Pb(2+)-induced vasogenic edema formation develops via a Flk-1-dependent mechanism and suggests that the vascular permeability caused by Pb(2+) is Flk-1 independent.

The effects of the oral, pan-VEGF-R kinase inhibitor CEP-7055 and chemotherapy in orthotopic models of glioblastoma and colon carcinoma in mice

“…Given the highly angiogenic nature of the VEGF-producing U87MG tumor and the effects of CEP-7055 on reducing tumor microvessel density, the observed reductions in edematous lesions observed in intracranial tumors with CEP-7055 administration alone and in combination with temozolomide are a reasonable experimental outcome in these studies. Similar observations for a reduction in VEGF-mediated cerebral edema have been observed with other VEGFR kinase inhibitors chemically related to CEP-7055 (42).…”

Does allicin combined with vitamin B-complex have superior potentials than alpha-tocopherol alone in ameliorating lead acetate-induced Purkinje cell alterations in rats? An immunohistochemical and ultrastructural study

“…Unhealthy, ballooned mitochondria, together with rarified matrices and ill-identified cristae, were observed in the cytoplasm of the Purkinje cells; these findings have already been described in hippocampal neurons in lead-treated rats [52]. It has been suggested that the principal influence of lead acetate on the cerebellum is the suppression of mitochondrial oxidative activity [24].…”

Endothelial Cell Permeability and Adherens Junction Disruption Induced by Junín Virus Infection

“…For example, TNF-α activates Fyn during sepsis, which results in the opening of the AJ, contributing to multiorgan failure, 17 and when P120-catenin mismanages the turnover of VE-cadherin, the permeability required for some kinds of tumor metastasis can occur. 32 VEGF signaling and Src kinase activation are also involved in many disease processes involving AJ disruption and inappropriate permeability, such as lead poisoning 15 and myocardial infarction. 15,33 It has also been shown that patients with dengue hemorrhagic fever have higher serum levels of VEGF and that Andes hantavirus-induced endothelial permeability is related to VEGFR2 signaling by Src; it can be decreased through Src and VEGFR2 inhibitors.…”

“…32 VEGF signaling and Src kinase activation are also involved in many disease processes involving AJ disruption and inappropriate permeability, such as lead poisoning 15 and myocardial infarction. 15,33 It has also been shown that patients with dengue hemorrhagic fever have higher serum levels of VEGF and that Andes hantavirus-induced endothelial permeability is related to VEGFR2 signaling by Src; it can be decreased through Src and VEGFR2 inhibitors. [34][35][36] However, we found no evidence in our JUNV model that disruption of AJs is through VEGFR2/Src-mediated signaling.…”

“…Although both types of junctions are involved in regulating vascular permeability, only AJs are ubiquitous throughout the vasculature, and there is substantial evidence that AJs and TJs are interconnected with AJs critical to TJ organization. [11][12][13] Furthermore, it has been shown that disruption of AJ alone is enough to dramatically increase permeability, 14 which contributes to pathogenesis of diseases, such as lead poisoning, 15 stroke, 16 sepsis, 17 and tumor metastasis. 18 The major protein component of endothelial AJs is vascular endothelial cadherin (VE-cadherin), a transmembrane protein that binds to intracellular proteins 19,20 in the catenin family, namely α, β, and γ, and P120.…”