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Effect of rhHB-EGF on the expression of hydrocephalus-related genes in vitro


Heparin binding epidermal growth factor like growth factor (HB-EGF) is a member of the epidermal growth factor family. The role of HB-EGF in cardiovascular disease such as atherosclerosis has been well-reported but its pertinence to cerebrovascular disease including hydrocephalus is unknown. In our laboratory human HB-EGF transgenic mice have been observed to demonstrate communicating hydrocephalus. The goal of this study was to find any difference in expression of three genes in vascular-lining cells under varying concentration of this growth factor.

Materials and methods

Two cell groups of murine microvascular endothelial and non-endothelial cell were exposed to 10, 100, and 1000 ng/ml of recombinant human HB-EGF (rhHB-EGF). Cellular response to rhHB-EGF was examined by quantitative real time reverse transcription polymerase chain reaction focusing on mRNA expression of vascular endothelial growth factor (VEGF), transforming growth factor β1 (TGF-β1), and tumor necrosis factor α (TNF-α), that may be associated with hydrocephalus. Also, VEGF protein levels in the culture supernatants of these cells to rhHB-EGF were measured by enzyme linked immunosorbent assay.


The results indicated that VEGF mRNA was significantly increased by 3–5 fold in endothelial cells treated with rhHB-EGF relative to the untreated control (p < 0.05). As compared to the control, mRNA expression of TNF-α in endothelial cells was significantly increased by 3, 9, and 13 fold at 12 h following 10, 100, and 1000 ng/ml of rhHB-EGF treatment, respectively (p < 0.05). Also, TGF-β1 mRNA in non-endothelial cells was significantly elevated by 4, 6, and 7 fold at 24 h following introduction of 10, 100, and 1000 ng/ml of rhHB-EGF, respectively (p < 0.05). When exposed to rhHB-EGF, VEGF protein levels in the conditioned media of endothelial cells were detectable but those in non-endothelial groups were undetectable over 1–6 h period.


These data demonstrated that rhHB-EGF led to induction of VEGF and TNF-α in microvascular endothelial cells and upregulation of TGF-β1 in non-endothelial cells from murine origin. Our findings support a hypothesis that human HB-EGF could activate multiple mouse genes reportedly linked to hydrocephalus and that it is worthwhile to assay these factors in cerebrospinal fluid of animal models for hydrocephalus.

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Correspondence to Joon W Shim.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Shim, J.W., Dudley, A., Klagsbrun, M. et al. Effect of rhHB-EGF on the expression of hydrocephalus-related genes in vitro. Fluids Barriers CNS 6 (Suppl 1), S5 (2009).

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