title: 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). Maintaining efficient cholesterol efflux is essential for normal cellular function. 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.
authors.affiliation: Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Longhou
authors.initials: L
authors.lastname: Fang
authors.forename: Soo-Ho
authors.initials: SH
authors.lastname: Choi
authors.forename: Ji Sun
authors.initials: JS
authors.lastname: Baek
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.forename: Felicidad
authors.initials: F
authors.lastname: Almazan
authors.forename: Florian
authors.initials: F
authors.lastname: Ulrich
authors.forename: Philipp
authors.initials: P
authors.lastname: Wiesner
authors.forename: Adam
authors.initials: A
authors.lastname: Taleb
authors.forename: Elena
authors.initials: E
authors.lastname: Deer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pattison
authors.forename: Jesús
authors.initials: J
authors.lastname: Torres-Vázquez
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Li
authors.forename: Yury I
authors.initials: YI
authors.lastname: Miller
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001808:Blood Vessels / Q000196:embryology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000032:analysis / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004625:Embryo, Nonmammalian / Q000098:blood supply / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D055503:Protein Multimerization; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; C553277:AUNIP protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D008075:Lipoproteins, HDL; D008563:Membrane Lipids; D029961:Zebrafish Proteins; D002784:Cholesterol; D040301:Vascular Endothelial Growth Factor Receptor-2