Excess HB-EGF, which promotes VEGF signaling, leads to hydrocephalus.

Joon W Shim,Michael Klagsbrun,Bonnie Blazer-Yost,Feng C Zhou,Johanna Sandlund,Joseph R Madsen,Mustafa Q Hameed

doi:10.1038/srep26794

Abstract

Heparin binding epidermal growth factor-like growth factor (HB-EGF) is an angiogenic factor mediating radial migration of the developing forebrain, while vascular endothelial growth factor (VEGF) is known to influence rostral migratory stream in rodents. Cell migratory defects have been identified in animal models of hydrocephalus; however, the relationship between HB-EGF and hydrocephalus is unclear. We show that mice overexpressing human HB-EGF with β-galactosidase reporter exhibit an elevated VEGF, localization of β-galactosidase outside the subventricular zone (SVZ), subarachnoid hemorrhage, and ventriculomegaly. In Wistar polycystic kidney rats with hydrocephalus, alteration of migratory trajectory is detected. Furthermore, VEGF infusions into the rats result in ventriculomegaly with an increase of SVZ neuroblast in rostral migratory stream, whereas VEGF ligand inhibition prevents it. Our results support the idea that excess HB-EGF leads to a significant elevation of VEGF and ventricular dilatation. These data suggest a potential pathophysiological mechanism that elevated HB-EGF can elicit VEGF induction and hydrocephalus.

Highlights

Hydrocephalus, characterized by dilatation of the cerebral ventricles due to excessive accumulation of cerebrospinal fluid (CSF), is classified into congenital and acquired hydrocephalus[1]
This in vitro experiment has shown that exogenous administration of human soluble Heparin binding epidermal growth factor-like growth factor (HB-EGF) induces endogenous vascular endothelial growth factor (VEGF) in the brain vascular endothelial cell
The results presented in this study support the idea that in order to regulate ventricular size HB-EGF confines its expression in the extra-subventricular zone (SVZ) of the cerebral cortex distant from the neurogenic niche in the postnatal forebrain

Summary

Introduction

Hydrocephalus, characterized by dilatation of the cerebral ventricles due to excessive accumulation of cerebrospinal fluid (CSF), is classified into congenital and acquired hydrocephalus[1]. This experiment has exhibited that mice expressing lacZ/βgal display a significantly elevated level of human HB-EGF mRNA in the brain in the presence of ventriculomegaly and SAH.

Results

Conclusion