Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane
Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV collagen assembly in the endothelial basement membrane
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DOI：
10.1182/blood-2010-10-313296
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发表时间：
2011-10-06
期刊：
影响因子：
20.3
通讯作者：
Germain, Stephane
中科院分区：
文献类型：
--
作者：
Bignon, Marine;Pichol-Thievend, Cathy;Germain, Stephane
发芽血管生成与广泛的细胞外基质（ECM）重塑有关。血管微环境的建立及其对毛细血管形成的影响的分子机制尚不清楚。因此，我们对维持在缺氧状态的内皮细胞的ECM进行了蛋白质组学分析，这是血管生成的主要刺激物。在这里，我们报道了赖氨酸氧化酶样蛋白-2 （LOXL2）作为缺氧靶标在新血管中表达并在内皮细胞外基质中积累的特性。LOXL2属于参与ECM交联的赖氨酸氧化酶家族。在Tg(fli1:egfp)y1斑马鱼胚胎中进行的敲除实验导致了节段间血管循环的缺乏，并证明了LOXL2参与了适当的毛细血管形成。通过功能损失和获得的进一步体外研究证实，LOXL2是三维纤维蛋白凝胶小管形成所必需的，并且证明该酶是ECM中胶原IV组装所必需的。此外，LOXL2缺失可下调细胞迁移和增殖。这些数据表明，LOXL2在内皮基层的组织和下游机械转导信号传导中起着重要作用。总之，我们的研究为LOXL2通过胶原IV支架调节血管生成的作用提供了第一个证据。(血。2011;118 (14):3979 - 3989)
Sprouting angiogenesis is associated with extensive extracellular matrix (ECM) remodeling. The molecular mechanisms involved in building the vascular microenvironment and its impact on capillary formation remain elusive. We therefore performed a proteomic analysis of ECM from endothelial cells maintained in hypoxia, a major stimulator of angiogenesis. Here, we report the characterization of lysyl oxidase-like protein-2 (LOXL2) as a hypoxia-target expressed in neovessels and accumulated in the endothelial ECM. LOXL2 belongs to the lysyl oxidase family of secreted enzymes involved in ECM crosslinking. Knockdown experiments in Tg(fli1:egfp)y1 zebrafish embryos resulted in lack of intersegmental vessel circulation and demonstrated LOXL2 involvement in proper capillary formation. Further investigation in vitro by loss and gain of function experiments confirmed that LOXL2 was required for tubulogenesis in 3D fibrin gels and demonstrated that this enzyme was required for collagen IV assembly in the ECM. In addition, LOXL2 depletion down-regulated cell migration and proliferation. These data suggest a major role for LOXL2 in the organization of endothelial basal lamina and in the downstream mechanotransductive signaling. Altogether, our study provides the first evidence for the role of LOXL2 in regulating angiogenesis through collagen IV scaffolding. (Blood. 2011;118(14):3979-3989)