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E.S. Colombo, P.G. McGuire, G. Menicucci, A. Das; Role of Hepatocyte Growth Factor in Retinal Vascular Development and Angiogenesis . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2331.
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Hepatocyte growth factor (HGF), acting through its receptor, c–met, is a cytokine whose role in promoting cell migration has been extensively documented in many cancer models. Additionally, reports indicate that HGF is increased in the vitreous and serum of patients with proliferative diabetic retinopathy. We have previously shown upregulation of HGF in retinas from a mouse model of retinal neovascularization. In addition, we have demonstrated increased protease expression and cell migration in isolated retinal endothelial cells in response to HGF. We further localized HGF and c–met in retinas during angiogenesis and utilized an HGF transgenic (HGF–TG) mouse to further determine its role in angiogenesis.
Immunohistochemistry was performed using anti–HGF and anti–c–met antibodies in the retina from day 17 mice with oxygen–induced retinopathy (OIR). Staining was visualized using confocal microscopy. To determine whether HGF overexpression induces alteration of the retinal vasculature, we examined retinas from adult HGF transgenic mice, (a generous gift of Dr. Glenn Merlino, NIH). Overexpression of HGF in the retina was confirmed by PCR. Blood vessels were visualized by staining endothelial cells with antibodies to CD31. Levels of protease gene expression were determined by semi–quantitative RT–PCR and by real–time RT–PCR from transgenic retinas compared to wild type controls.
HGF and c–Met were localized to vascular endothelial cells in the OIR model. In HGF–TG mice, CD31 staining revealed large, dilated blood vessels in the nerve fiber layer and some abnormal vessels on the vitreal side of the inner limiting membrane. Analysis of protease gene expression indicated an increase in urokinase mRNA levels and a mild increase in MMP 2 mRNA levels, compared to wild type control mice.
Specific localization of HGF to angiogenic vessels in retinas from the OIR model indicates its involvement in retinal angiogenesis. The retinal phenotype seen in HGF–TG mice implies endothelial cell hyperplasia indicative of abnormal retinal vasculature. Overexpression of HGF induces the proangiogenic factors, urokinase and MMP 2. Our findings point toward HGF as an important mediator of retinal angiogenesis and represent a potential target for therapeutic intervention.
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