A collagen Vα1-derived fragment inhibits FGF-2 induced-angiogenesis by modulating endothelial cells plasticity through its heparin-binding site
A collagen Vα1-derived fragment inhibits FGF-2 induced-angiogenesis by modulating endothelial cells plasticity through its heparin-binding site
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DOI：
10.1016/j.matbio.2020.07.001
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发表时间：
2020-12-01
期刊：
影响因子：
6.9
通讯作者：
Ruggiero, Florence
中科院分区：
文献类型：
--
作者：
Jia, Tao;Vaganay, Elisabeth;Ruggiero, Florence
V型胶原（ColV）是内皮基底膜区的组分。在血管生成过程中，细胞外基质重塑导致活性蛋白片段的释放，这些活性蛋白片段显示促血管生成或抗血管生成特性。后者通常通过其肝素结合位点发挥其活性。我们以前的特点是ColV α 1衍生的片段，称为HEPV，含有肝素和硫酸乙酰肝素链的高亲和力结合位点。在这里，我们表明，HEPV结合FGF2通过其肝素结合位点。使用体外和体内血管生成试验，我们表明，HEPV，但不是HEPV突变体在肝素结合位点，抑制FGF 2依赖性血管生成。相反，HEPV不与VEGFA结合，对VEGFA介导的血管生成没有影响。在3D胶原凝胶中，HEPV的加入消除了由FGF2诱导的内皮细胞侵袭和发芽。有趣的是，体内实验表明，HEPV抗血管生成活性与内皮细胞间质转化（EndMT）标志物的出现有关。总之，这些发现表明，ColV α 1衍生片段HEPV作为一种抗血管生成因子，通过调节内皮细胞可塑性来抑制FGF 2介导的血管生成。以前的观察表明，ColV过表达负调节病理性血管生成是无法解释的。我们的数据提供了可能的分子机制的见解。(C)2020爱思唯尔B.V.保留所有权利。
Type V collagen (ColV) is a component of the endothelial basement membrane zone. During angiogenesis, extracellular matrix remodelling results in the release of active protein fragments that display pro- or anti-angiogenic properties. The latter often exert their activity through their heparin-binding site. We previously characterized a ColV alpha 1-derived fragment called HEPV that contains a high affinity-binding site for heparin and heparan sulphate chains. Here we show that HEPV binds to FGF2 through its heparin-binding site. Using in vitro and in vivo angiogenesis assays, we show that HEPV but not the HEPV mutant at the heparin-binding site, inhibits FGF2-dependant angiogenesis. On the opposite, HEPV does not bind to VEGFA and has no effect on VEGFA-mediated angiogenesis. In 3D collagen gels, the addition of HEPV abrogates endothelial cell invasion and sprouting induced by FGF2. Interestingly, in vivo experiments reveal that HEPV anti-angiogenic activity is associated with the appearance of endothelial to mesenchymal transition (EndMT) markers. Together, these findings indicate that the ColV alpha 1-derived fragment HEPV functions as an anti-angiogenic factor that represses FGF2-mediated angiogenesis through the regulation of endothelial cell plasticity. Previous observations showing that ColV overexpression negatively regulates pathological angiogenesis were left unexplained. Our data provide insights into the possible molecular mechanisms. (C) 2020 Elsevier B.V. All rights reserved.