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Inhibition of retinal neovascularization by gene transfer of small interfering RNA targeting HIF‐1α and VEGF
Author(s) -
Jiang Jian,
Xia XiaoBo,
Xu HuiZhuo,
Xiong Yu,
Song WeiTao,
Xiong SiQi,
Li Yan
Publication year - 2009
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21566
Subject(s) - small interfering rna , vascular endothelial growth factor , transfection , neovascularization , retinal , angiogenesis , umbilical vein , in vivo , cancer research , vascular endothelial growth factor a , genetic enhancement , gene silencing , in vitro , biology , microbiology and biotechnology , chemistry , cell culture , vegf receptors , gene , biochemistry , genetics
Abstract Retinal neovascularization (NV) occurs in various ocular disorders including proliferative diabetic retinopathy, retinopathy of prematurity and secondary neovascular glaucoma, which often result in blindness. Vascular endothelial growth factor (VEGF) is an essential growth factor for angiogenesis, and is particularly regulated by hypoxia inducible factor‐1α (HIF‐1α) under hypoxic conditions. Therefore, HIF‐1α and VEGF could provide targets for therapeutic intervention on retinal NV. In this study, we investigated the inhibitory effects of small interfering RNA (siRNA) targeting HIF‐1α and VEGF on the expression of HIF‐1α and VEGF in human umbilical vein endothelial cells (HUVEC) in vitro and on retinal NV in vivo. siRNA‐expressing plasmids targeting human HIF‐1α (HIF‐1α siRNA) and human VEGF 165 (VEGF siRNA) were constructed. They were transfected and co‐transfected to HUVEC and C57BL/6J mice of ischemic retinopathy model. HIF‐1α siRNA and VEGF siRNA specifically downregulated HIF‐1α and VEGF at both mRNA and protein levels in vitro and in vivo. Neovascular tufts and neovascular nuclei were decreased in gene therapy group compared to control hypoxia group. Co‐transfection of HIF‐1α siRNA and VEGF siRNA resulted in maximal effects on VEGF suppression in vitro and in vivo. It also manifested the maximal inhibitory effect on retinal NV. These results indicate that the application of HIF‐1α siRNA and VEGF siRNA technology holds great potential as a novel therapeutic for retinal NV. J. Cell. Physiol. 218: 66–74, 2009. © 2008 Wiley‐Liss, Inc.