Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome
Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome
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DOI：
10.1038/nature02320
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发表时间：
2004-02-12
期刊：
影响因子：
64.8
通讯作者：
Wang, Q
中科院分区：
文献类型：
--
作者：
Tian, XL;Kadaba, R;Wang, Q
血管生成因子对血管生成的启动和血管网络的维持至关重要（1）。在这里，我们使用人类遗传学作为鉴定血管生成因子VG 5 Q的方法，并进一步确定血管疾病Klippel-Trenaunay综合征（KTS）患者中VG 5 Q的两种遗传缺陷（2，3）。一种突变是染色体易位t（5;11），其增加VG 5 Q转录。第二个是在5名KTS患者中发现的突变E133 K，但在200名匹配的对照中没有发现。VG 5 Q蛋白作为一种有效的促血管生成因子，促进血管生成，抑制VG 5 Q表达可抑制血管形成。E133 K是一种功能性突变，可显著增强VG 5 Q的血管生成作用。VG 5 Q在血管中显示出强表达，并在血管形成开始时分泌。VG 5 Q可以与内皮细胞结合并促进细胞增殖，这表明它可能以自分泌方式起作用。我们还证明了VG 5 Q与另一种分泌的血管生成因子TWEAK（也称为TNFSF 12）的直接相互作用（4，5）。这些结果将VG 5 Q定义为血管生成因子，将VG 5 Q确定为KTS的易感基因，并表明血管生成增加是KTS的分子致病机制。
Angiogenic factors are critical to the initiation of angiogenesis and maintenance of the vascular network(1). Here we use human genetics as an approach to identify an angiogenic factor, VG5Q, and further define two genetic defects of VG5Q in patients with the vascular disease Klippel-Trenaunay syndrome (KTS)(2,3). One mutation is chromosomal translocation t(5;11), which increases VG5Q transcription. The second is mutation E133K identified in five KTS patients, but not in 200 matched controls. VG5Q protein acts as a potent angiogenic factor in promoting angiogenesis, and suppression of VG5Q expression inhibits vessel formation. E133K is a functional mutation that substantially enhances the angiogenic effect of VG5Q. VG5Q shows strong expression in blood vessels and is secreted as vessel formation is initiated. VG5Q can bind to endothelial cells and promote cell proliferation, suggesting that it may act in an autocrine fashion. We also demonstrate a direct interaction of VG5Q with another secreted angiogenic factor, TWEAK (also known as TNFSF12)(4,5). These results define VG5Q as an angiogenic factor, establish VG5Q as a susceptibility gene for KTS, and show that increased angiogenesis is a molecular pathogenic mechanism of KTS.