Journal
COMMUNICATIONS BIOLOGY
Volume 3, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s42003-020-1113-z
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Funding
- BrightFocus Foundation
- Retinal Research Foundation
- Sarah Campbell Blaffer Endowment in Ophthalmology
- NIH [2P30EY002520]
- Research to Prevent Blindness
- NATIONAL EYE INSTITUTE [P30EY002520] Funding Source: NIH RePORTER
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Many patients of choroidal neovascularization (CNV) are unresponsive to the current anti-VEGF treatment. The mechanisms for anti-VEGF resistance are poorly understood. We explore the unique property of the apolipoprotein A-I (apoA-I) binding protein (AIBP) that enhances cholesterol efflux from endothelial cells and macrophages to thereby limit angiogenesis and inflammation to tackle anti-VEGF resistance in CNV. We show that laser-induced CNV in mice with increased age showed increased resistance to anti-VEGF treatment, which correlates with increased lipid accumulation in macrophages. The combination of AIBP/apoA-I and anti-VEGF treatment overcomes anti-VEGF resistance and effectively suppresses CNV. Furthermore, macrophage depletion in old mice restores CNV sensitivity to anti-VEGF treatment and blunts the synergistic effect of combination therapy. These results suggest that cholesterol-laden macrophages play a critical role in inducing anti-VEGF resistance in CNV. Combination therapy by neutralizing VEGF and enhancing cholesterol removal from macrophages is a promising strategy to combat anti-VEGF resistance in CNV. By combining advanced age and laser photocoagulation, Zhu et al. establish a novel CNV model of anti-VEGF resistance. They show that lipid accumulation in old macrophages promote angiogenesis, and that apoA-I binding protein (AIBP) inhibits angiogenesis by reducing this lipid accumulation. They further show that the combination of AIBP/apoA-I and anti-VEGF treatment overcomes anti-VEGF resistance and effectively suppresses CNV.
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