Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
Nature. 2013 Jun 6;498(7452):118-22. doi: 10.1038/nature12166. Epub 2013 May 29.
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.
胆固醇是细胞的结构组成部分，对于正常的细胞功能是不可或缺的，尽管其过量通常会导致异常增殖、迁移、炎症反应和/或细胞死亡。为了防止胆固醇过载，ATP 结合盒（ABC）转运蛋白将胆固醇从细胞内转运到载脂蛋白 A-I（apoA-I）和载脂蛋白 A-I 含量高的密度脂蛋白（HDL）。维持有效的胆固醇外排对于正常的细胞功能至关重要。然而，胆固醇外排在血管生成中的作用及其局部调节因子的身份知之甚少。在这里，我们表明载脂蛋白 A-I 结合蛋白（AIBP）加速胆固醇从内皮细胞向 HDL 的外排，从而调节血管生成。AIBP 和 HDL 介导的胆固醇耗竭减少脂筏，干扰 VEGFR2（也称为 KDR）二聚化和信号转导，并抑制体外血管内皮生长因子诱导的血管生成和小鼠主动脉新生血管形成。值得注意的是，Aibp，一种人类 AIBP 的斑马鱼同源物，调节胚胎斑马鱼血管系统的膜脂序，并作为血管生成的非细胞自主调节因子发挥作用。aibp 敲低导致发芽/分支血管生成失调，而强制表达 Aibp 则抑制血管生成。Abca1（也称为 Abca1a）Abcg1 缺陷胚胎中的血管生成失调表型，Aibp 缺陷和 Abca1Abcg1 缺陷胚胎中的胆固醇水平升高。我们的研究结果表明，分泌的 AIBP 可正向调节内皮细胞中的胆固醇外排，有效的胆固醇外排对于适当的血管生成至关重要。
