Secretogranin III as a disease-associated ligand for antiangiogenic therapy of diabetic retinopathy.
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.
Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL 33136.
Michelle E
ME
LeBlanc
Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL 33136.
Weiwen
W
Wang
Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL 33136.|Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai 200433, China.
Xiuping
X
Chen
School of Life Sciences, University of Nevada Las Vegas, Las Vegas, NV 89154.
Nora B
NB
Caberoy
Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL 33136.
Feiye
F
Guo
Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL 33136.
Chen
C
Shen
Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL 33136.|Department of Ophthalmology, Zhengzhou Eye Hospital, Zhengzhou 450000, Henan, China.
Yanli
Y
Ji
Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL 33136.|School of Public Health, Xinxiang Medical University, Xinxiang, Henan 453003, China.|Everglades Biopharma, Miami, FL 33156.
Hong
H
Tian
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.
Hui
H
Wang
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.
Rui
R
Chen
Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, FL 33136 w.li@med.miami.edu.|Vascular Biology Institute, University of Miami School of Medicine, Miami, FL 33136.
Wei
0000-0001-9566-8764
W
Li
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002199:Capillary Permeability; D002864:Chromogranins / Q000037:antagonists & inhibitors / Q000502:physiology*; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D059014:High-Throughput Nucleotide Sequencing; D008024:Ligands; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology
D020533:Angiogenesis Inhibitors; D002864:Chromogranins; D008024:Ligands; D042461:Vascular Endothelial Growth Factor A; C506167:secretogranin III