Combination of apolipoprotein-A-I/apolipoprotein-A-I binding protein and anti-VEGF treatment overcomes anti-VEGF resistance in choroidal neovascularization in mice

• Published in: Communications biology Vol. 3; no. 1; p. 386
• Main Authors: Zhu, Lingping, Parker, Mackenzie, Enemchukwu, Nduka, Shen, Megan, Zhang, Guogang, Yan, Qing, Handa, James T., Fang, Longhou, Fu, Yingbin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-07-2020; Nature Publishing Group
• Subjects: 13/106; 14/19; 14/32; 631/378/2613; 64/60; 692/699/3161/1626; Angiogenesis; Apolipoprotein A; Apolipoprotein A-I; Apolipoproteins; Biology; Biomedical and Life Sciences; Cholesterol; Endothelial cells; Life Sciences; Lipids; Macrophages; Proteins; Vascular endothelial growth factor; Vascularization
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-020-1113-z

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.