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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Apolipoprotein A-I / administration & dosage
  • Apolipoprotein A-I / therapeutic use*
  • Cell Membrane / metabolism
  • Cholesterol / metabolism
  • Choroid / metabolism
  • Choroidal Neovascularization / drug therapy*
  • Drug Resistance
  • Drug Therapy, Combination
  • Female
  • Humans
  • Macrophages / drug effects
  • Male
  • Mice
  • Neovascularization, Pathologic / drug therapy
  • Phosphoproteins / administration & dosage
  • Phosphoproteins / therapeutic use*
  • Racemases and Epimerases / administration & dosage
  • Racemases and Epimerases / therapeutic use*
  • Retina / metabolism
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*


  • Apolipoprotein A-I
  • C5FW ORF protein, Canis familiaris
  • Phosphoproteins
  • Vascular Endothelial Growth Factor A
  • Cholesterol
  • Naxe protein, mouse
  • Racemases and Epimerases