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.
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Abbreviations
- AF488-IB4:
-
Alexa Fluor 488-isolectin B4
- CNV:
-
Choroidal neovascularization
- DR:
-
Diabetic retinopathy
- EC:
-
Endothelial cell
- ERG:
-
Electroretinography
- FA:
-
Fluorescein angiography
- hAb:
-
Humanized antibody
- hFab:
-
Humanized or human antibody Fab fragment
- HRMVEC:
-
Human retinal microvascular endothelial cell
- IHC:
-
Immunohistochemistry
- OCT:
-
Optical coherence tomography
- OCTC:
-
Optimal cutting temperature compound
- OIR:
-
Oxygen-induced retinopathy
- RNV:
-
Retinal neovascularization
- ROP:
-
Retinopathy of prematurity
- Scg3:
-
Secretogranin III
- Scg3R:
-
Secretogranin III receptor
- VEGF:
-
Vascular endothelial growth factor
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Acknowledgements
The authors thank Drs. Yingbin Fu and Philp Rosenfeld for scientific discussion and Dr. Yuqin Wang for technical support. Ralph Nichols for TEM at the Imaging Core Facility, Cullen Eye Institute, Baylor College of Medicine.
Funding
This work was supported by NIH R01EY027749 (WL), R24EY028764 (WL and KAW), R24EY028764-01A1S1 (WL and KAW), R43EY031238 (HT, KAW and WL), R43EY031643 (HT), R41EY027665 (WL and HT), American Diabetes Association 1-18-IBS-172 (WL), NIH P30EY002520, Knights Templar Eye Foundation Endowment in Ophthalmology (WL) and an unrestricted institutional grant from Research to Prevent Blindness (RPB) to Department of Ophthalmology, Baylor College of Medicine.
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CD, PW, LJ and CH designed and performed experiments and data analyses. YH and EZ provided technical support. HT provided reagents and technical support. AB, IP, GS and KW provided scientific support. WL conceived and supervised the project and experiments and analyzed data. CD and WL wrote and revised manuscript. KW revised manuscript.
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HT and WL are shareholders of Everglades Biopharma, LLC and LigandomicsRx, LLC. The remaining authors declare no competing financial interests.
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Dai, C., Waduge, P., Ji, L. et al. Secretogranin III stringently regulates pathological but not physiological angiogenesis in oxygen-induced retinopathy. Cell. Mol. Life Sci. 79, 63 (2022). https://doi.org/10.1007/s00018-021-04111-2
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DOI: https://doi.org/10.1007/s00018-021-04111-2