Publication Date
1-10-2022
Journal
Cellular and Molecular Life Sciences
DOI
10.1007/s00018-021-04111-2
PMID
35006382
PMCID
PMC9007175
PubMedCentral® Posted Date
1-10-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Angiogenesis Inhibitors, Animals, Capillaries, Chromogranins, Disease Models, Animal, Immunoglobulin Fab Fragments, Mice, Mice, Inbred C57BL, Mice, Knockout, Neovascularization, Pathologic, Oxygen, Receptors, Vascular Endothelial Growth Factor, Recombinant Fusion Proteins, Retinal Neovascularization, Retinopathy of Prematurity, Vascular Endothelial Growth Factor A
Abstract
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.
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Endocrine System Diseases Commons, Endocrinology, Diabetes, and Metabolism Commons, Eye Diseases Commons, Medical Sciences Commons, Ophthalmology Commons, Optometry Commons
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