TY - JOUR
T1 - Secretogranin III as a disease-associated ligand for antiangiogenic therapy of diabetic retinopathy
AU - LeBlanc, Michelle E.
AU - Wang, Weiwen
AU - Chen, Xiuping
AU - Caberoy, Nora B.
AU - Guo, Feiye
AU - Shen, Chen
AU - Ji, Yanli
AU - Tian, Hong
AU - Wang, Hui
AU - Chen, Rui
AU - Li, Wei
N1 - Funding Information:
We thank Keith Webster, Philip Rosenfeld, Jian-Xing Ma, Henry Flynn, and William Smiddy for scientific advice and discussion; Feng Wang for NGS data analysis; William Feuer for advice on statistical analysis; Gabriela Alvarado, Akhalesh Shakya, Chenming Zhang, Robert Liu, and Jisu Yu for technical help; Gabriel Gaidosh for confocal service; Megan Brewer for cartoon drawing; Fanglian Zhang and Ron Wen for instrument support; and Pickersgill and Andersen (Life Science Editors) and Abigail Hackam for manuscript editing. This work was supported by the National Institutes of Health (grants. R01GM094449, R21HD075372, and R21EY027065 to W. Li and grant P30-EY014801), BrightFocus Foundation (grant M2012026 to W. Li), an institutional grant and a Special Scholar Award (W. Li) from Research to Prevent Blindness, and an American Heart Association Predoctoral Fellowship (14PRE18310014 and 16PRE27250308 to M.E. LeBlanc). Patent applications are pending.
Publisher Copyright:
© 2017 LeBlanc et al.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Diabetic retinopathy (DR) is a leading cause of vision loss with retinal vascular leakage and/or neovascularization. Current antiangiogenic therapy against vascular endothelial growth factor (VEGF) has limited efficacy. In this study, we applied a new technology of comparative ligandomics to diabetic and control mice for the differential mapping of disease-related endothelial ligands. Secretogranin III (Scg3) was discovered as a novel disease-associated ligand with selective binding and angiogenic activity in diabetic but not healthy vessels. In contrast, VEGF bound to and induced angiogenesis in both diabetic and normal vasculature. Scg3 and VEGF signal through distinct receptor pathways. Importantly, Scg3-neutralizing antibodies alleviated retinal vascular leakage in diabetic mice with high efficacy. Furthermore, anti-Scg3 prevented retinal neovascularization in oxygen-induced retinopathy mice, a surrogate model for retinopathy of prematurity (ROP). ROP is the most common cause of vision impairment in children, with no approved drug therapy. These results suggest that Scg3 is a promising target for novel antiangiogenic therapy of DR and ROP.
AB - Diabetic retinopathy (DR) is a leading cause of vision loss with retinal vascular leakage and/or neovascularization. Current antiangiogenic therapy against vascular endothelial growth factor (VEGF) has limited efficacy. In this study, we applied a new technology of comparative ligandomics to diabetic and control mice for the differential mapping of disease-related endothelial ligands. Secretogranin III (Scg3) was discovered as a novel disease-associated ligand with selective binding and angiogenic activity in diabetic but not healthy vessels. In contrast, VEGF bound to and induced angiogenesis in both diabetic and normal vasculature. Scg3 and VEGF signal through distinct receptor pathways. Importantly, Scg3-neutralizing antibodies alleviated retinal vascular leakage in diabetic mice with high efficacy. Furthermore, anti-Scg3 prevented retinal neovascularization in oxygen-induced retinopathy mice, a surrogate model for retinopathy of prematurity (ROP). ROP is the most common cause of vision impairment in children, with no approved drug therapy. These results suggest that Scg3 is a promising target for novel antiangiogenic therapy of DR and ROP.
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U2 - 10.1084/jem.20161802
DO - 10.1084/jem.20161802
M3 - Article
C2 - 28330905
AN - SCOPUS:85021901880
VL - 214
SP - 1029
EP - 1047
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 4
ER -