Control of angiogenesis by AIBP-mediated cholesterol efflux.
Control of angiogenesis by AIBP-mediated cholesterol efflux.
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胆固醇是细胞的结构成分，对于正常的细胞功能是必不可少的，但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）转运蛋白介导胆固醇从细胞流出至载脂蛋白A-I（ApoA-I）和含ApoA-I的高密度脂蛋白（HDL）。维持有效的胆固醇流出对于正常的细胞功能是必不可少的。然而，胆固醇流出在血管生成中的作用及其局部调节剂的身份知之甚少。在这里，我们表明，载脂蛋白A-I结合蛋白（AIBP）加速胆固醇流出内皮细胞（EC）的HDL，从而调节血管生成。AIBP/HDL介导的胆固醇消耗减少脂筏，干扰VEGFR 2二聚化和信号传导，并抑制VEGF诱导的体外血管生成和小鼠离体主动脉新生血管形成。值得注意的是，Aibp调节胚胎斑马鱼血管系统中的膜脂质秩序，并作为斑马鱼血管生成的非细胞自主调节因子发挥作用。Aibp敲低导致芽生/分支血管生成失调，而强制Aibp表达抑制血管生成。在Abca 1/Abcg 1缺陷的胚胎中，血管生成失调是表型模仿的，并且在Aibp缺陷和Abca 1/Abcg 1缺陷的胚胎中胆固醇水平增加。我们的研究结果表明，分泌型AIBP积极调节EC的胆固醇流出，有效的胆固醇流出是正确的血管生成的关键。
Cholesterol is a structural component of the cell, indispensable for normal cellular function, but 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 to 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 (EC) to HDL and thereby regulates angiogenesis. AIBP/HDL-mediated cholesterol depletion reduces lipid rafts, interferes with VEGFR2 dimerization and signaling, and inhibits VEGF-induced angiogenesis in vitro and mouse aortic neovascularization ex vivo. Remarkably, Aibp regulates the membrane lipid order in embryonic zebrafish vasculature and functions as a non-cell autonomous regulator of zebrafish angiogenesis. Aibp knockdown results in dysregulated sprouting/branching angiogenesis, while forced Aibp expression inhibits angiogenesis. Dysregulated angiogenesis is phenocopied in Abca1/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 EC and that effective cholesterol efflux is critical for proper angiogenesis.