Zhu Lingping, Parker Mackenzie, Enemchukwu Nduka, Shen Megan, Zhang Guogang, Yan Qing, Handa James T, Fang Longhou, Fu Yingbin
The Xiangya Hospital of Central South University, 87 Xiangya Road, Changsha Kaifu District, Changsha, Hunan, China.
Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist DeBakey Heart and Vascular Center, Houston Methodist, Houston, TX, 77030, USA.
Commun Biol. 2020 Jul 16;3(1):386. 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.
许多脉络膜新生血管（CNV）患者对当前的抗血管内皮生长因子（VEGF）治疗无反应。抗VEGF耐药的机制尚不清楚。我们探索了载脂蛋白A-I（apoA-I）结合蛋白（AIBP）的独特特性，该蛋白可增强胆固醇从内皮细胞和巨噬细胞的流出，从而限制血管生成和炎症，以解决CNV中的抗VEGF耐药问题。我们发现，随着年龄增长，激光诱导的小鼠CNV对抗VEGF治疗的耐药性增加，这与巨噬细胞中脂质积累增加相关。AIBP/apoA-I与抗VEGF治疗联合可克服抗VEGF耐药并有效抑制CNV。此外，老年小鼠中的巨噬细胞耗竭可恢复CNV对抗VEGF治疗的敏感性，并削弱联合治疗的协同效应。这些结果表明，富含胆固醇的巨噬细胞在诱导CNV抗VEGF耐药中起关键作用。通过中和VEGF和增强巨噬细胞胆固醇清除的联合治疗是对抗CNV抗VEGF耐药的一种有前景的策略。
