Secretogranin III stringently regulates pathological but not physiological angiogenesis in oxygen-induced retinopathy
| Autor: | Chang Dai, Prabuddha Waduge, Liyang Ji, Chengchi Huang, Ye He, Hong Tian, Elizabeth Zuniga-Sanchez, Amit Bhatt, Iok-Hou Pang, Guanfang Su, Keith A. Webster, Wei Li |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Pharmacology
Mice Knockout Vascular Endothelial Growth Factor A Neovascularization Pathologic Recombinant Fusion Proteins Angiogenesis Inhibitors Cell Biology Retinal Neovascularization Article Capillaries Mice Inbred C57BL Oxygen Cellular and Molecular Neuroscience Disease Models Animal Immunoglobulin Fab Fragments Mice Receptors Vascular Endothelial Growth Factor Chromogranins Molecular Medicine Animals Retinopathy of Prematurity Molecular Biology |
| Zdroj: | Cell Mol Life Sci |
| Popis: | Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized Scg3 binding exclusively to disease-related disorganized retinal neovessels and neovascular tufts, whereas VEGF bound to both disorganized and well-organized neovessels. Homozygous deletion of the Scg3 gene showed undetectable effects on physiological retinal neovascularization but markedly reduced the severity of OIR-induced pathological angiogenesis. Furthermore, anti-Scg3 humanized antibody Fab (hFab) inhibited pathological angiogenesis with similar efficacy to anti-VEGF aflibercept. Aflibercept dose-dependently blocked physiological angiogenesis in neonatal retinas, whereas anti-Scg3 hFab was without adverse effects at any dose and supported a therapeutic window at least 10X wider than that of aflibercept. Therefore, Scg3 stringently regulates pathological but not physiological angiogenesis, and anti-Scg3 hFab satisfies essential criteria for development as a safe and effective disease-targeted anti-angiogenic therapy for ROP. |
| Databáze: | OpenAIRE |
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