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Michelle Elizabeth LeBlanc, Weiwen Wang, XIUPING CHEN, yanli ji, chen shen, Vivianne Gonzalez, Megan Brewer, Jian-Xing (Jay) Ma, Rong Wen, Wei Li; The regulatory role of hepatoma-derived growth factor as an angiogenic factor in the eye. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4999.
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© ARVO (1962-2015); The Authors (2016-present)
Hepatoma-derived growth factor (HDGF) is a mitogen previously reported to promote endothelial proliferation and neuronal survival. However, the role of HDGF and its expression in the eye have not been described. We hypothesized that HDGF is expressed in the eye and functions as a retinal angiogenic factor.
HDGF expression in the mouse retina was characterized using immunohistochemistry and Western blot analyses. We analyzed the proliferation (HDGF 100 ng/ml, n=7), migration (HDGF 500 ng/ml, n=3) and permeability (HDGF 100 ng/ml, n=3) of human retinal microvascular endothelial cells (HRMVECs) to determine the angiogenic activity of HDGF in vitro. Corneal pocket assay independently verified HDGF (1 µg/µl) as an angiogenic factor in vivo (n=5). Evans blue dye was used to assess acute retinal leakage in vivo induced by intravitreal injection of HDGF (0.5 µg/eye, n=4). To determine whether HDGF expression was altered in disease conditions, we generated animal models of laser-induced choroid neovascularization (LCNV) and oxygen-induced retinopathy (OIR). Western blot was used to quantify HDGF expression in the retina and vitreous fluid of diseased or healthy mice.
Immunohistochemistry showed HDGF was predominantly expressed in the inner nuclear layer, outer nuclear layer and photoreceptor outer segments. Minor HDGF signals were found in retinal ganglion cells and photoreceptor inner segments. Few signals were detected in the inner and outer plexiform layers. In vitro functional assays showed HDGF induced the proliferation (p<0.05), migration (p<0.05) and permeability (p<0.05) of HRMVECs. Corneal pocket assay indicated HDGF is sufficient to stimulate angiogenesis (p<0.01; 22.0+/-3.82 versus 2.0+/-1.4). Intravitreal injection of HDGF significantly promoted retinal vascular leakage (p<0.01; 5.11+/-1.09 versus 0.8+/-0.14). HDGF expression was not significantly altered in the retina or vitreous fluid of LCNV (n=3) or OIR mice (n=6-7).
These results suggest that HDGF without a classical signal peptide can be secreted through an unconventional pathway and regulate angiogenesis in the retinal vasculature. The results of corneal pocket assay suggest that the functional activity of HDGF is not limited to retinal vasculature. The ability of HDGF to induce retinal permeability in vivo implicates that this factor may play a role in retinal vascular diseases.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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