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Control of angiogenesis by AIBP-mediated cholesterol efflux

Abstract

Cholesterol is a structural component of the cell and is indispensable for normal cellular function, although its excess often leads to abnormal proliferation, migration, inflammatory responses and/or cell death. To prevent cholesterol overload, ATP-binding cassette (ABC) transporters mediate cholesterol efflux from the cells to apolipoprotein A-I (apoA-I) and the apoA-I-containing high-density lipoprotein (HDL)1,2,3. Maintaining efficient cholesterol efflux is essential for normal cellular function4,5,6. However, the role of cholesterol efflux in angiogenesis and the identity of its local regulators are poorly understood. Here we show that apoA-I binding protein (AIBP) accelerates cholesterol efflux from endothelial cells to HDL and thereby regulates angiogenesis. AIBP- and HDL-mediated cholesterol depletion reduces lipid rafts, interferes with VEGFR2 (also known as KDR) dimerization and signalling and inhibits vascular endothelial growth factor-induced angiogenesis in vitro and mouse aortic neovascularization ex vivo. Notably, Aibp, a zebrafish homologue of human AIBP, regulates the membrane lipid order in embryonic zebrafish vasculature and functions as a non-cell-autonomous regulator of angiogenesis. aibp knockdown results in dysregulated sprouting/branching angiogenesis, whereas forced Aibp expression inhibits angiogenesis. Dysregulated angiogenesis is phenocopied in Abca1 (also known as Abca1a) Abcg1-deficient embryos, and cholesterol levels are increased in Aibp-deficient and Abca1 Abcg1-deficient embryos. Our findings demonstrate that secreted AIBP positively regulates cholesterol efflux from endothelial cells and that effective cholesterol efflux is critical for proper angiogenesis.

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Figure 1: Role of AIBP in cholesterol efflux from endothelial cells and in vitro angiogenesis.
Figure 2: Effect of AIBP on HUVEC lipid rafts, VEGFR2 localization, dimerization and signalling.
Figure 3: Effect of Aibp deficiency on zebrafish cholesterol, membrane lipid order, Vegfr2 signalling and angiogenesis.
Figure 4: Effect of Aibp and Abca1 Abcg1 deficiency on zebrafish angiogenesis.

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Acknowledgements

We thank D. Traver, N. Chi, J. Witztum, R. Klemke, D. Yelon, T. Handel, K. Stoletov, W. Clements, C. Pouget, Z. Garavito-Aguilar, A. Ablooglu, R. Zhang, X. Yang, M. Angert, K. Pestonjamasp and J. Santini (University of California, San Diego), C. Hedrick, K. Ley, D. Sag, P. Sundd and A. Wu (La Jolla Institute for Allergy and Immunology), S. Trzaska (New York University), S. J. Du (University of Maryland), B. Schmid and C. Haass (Ludwig-Maximilians-University München), D. Owen and A. Magenau (University of New South Wales), A. Siekmann (Max Planck Institute for Molecular Biomedicine) and C. Binder (Medical University of Vienna) for discussions, technical assistance and/or for providing reagents and access to equipment for this study. The project was supported by the NIH grants HL093767 (Y.I.M.), HL055798 (Y.I.M.) and HL114734 (L.F.), and the fellowship 18FT-0137 from the UC Tobacco-Related Disease Program (L.F.), as well as the UCSD Neuroscience Microscopy Facility Grant P30 NS047101. The authors declare no conflicts of interests.

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L.F. and Y.I.M. conceived the project, designed the experiments and wrote the manuscript. J.T.-V. made important intellectual contributions and helped revise the manuscript. L.F. performed the majority of the experiments. S.-H.C., J.S.B., C.L., F.A., F.U., P.W., A.T., E.D., J.P., A.C.L. performed experiments and/or provided research assistance.

Corresponding author

Correspondence to Yury I. Miller.

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Fang, L., Choi, SH., Baek, J. et al. Control of angiogenesis by AIBP-mediated cholesterol efflux. Nature 498, 118–122 (2013). https://doi.org/10.1038/nature12166

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