Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis.
Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis.
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DOI：
10.1172/jci21152
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发表时间：
2004-10
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通讯作者：
Kazuhide Watanabe;Yasuhiro Hasegawa;H. Yamashita;K. Shimizu;Yuanying Ding;M. Abe;H. Ohta;K. Imagawa;K. Hojo;H. Maki;H. Sonoda;Yasufumi Sato
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作者：
Kazuhide Watanabe;Yasuhiro Hasegawa;H. Yamashita;K. Shimizu;Yuanying Ding;M. Abe;H. Ohta;K. Imagawa;K. Hojo;H. Maki;H. Sonoda;Yasufumi Sato
负反馈是一种重要的生理调节机制，但还没有建立这样的血管生成调节器。在这里，我们报告了一种新的血管生成抑制剂，诱导内皮细胞（EC）的血管生成因子和抑制血管生成的自分泌方式。我们已经进行了cDNA微阵列分析，调查VEGF诱导的基因在人类内皮细胞。我们确定了一个这样的基因，KIAA 1036，其功能尚未确定。重组蛋白抑制迁移，增殖和网络形成的EC以及在体内血管生成。这种抑制作用对EC具有选择性，因为该蛋白质不影响平滑肌细胞或成纤维细胞的迁移。特异性消除内皮细胞中KIAA 1036的表达恢复了它们对更高浓度VEGF的反应性。KIAA 1036的表达对内皮细胞具有选择性，缺氧或TNF-α可抑制其诱导表达。由于该分子优先在EC中表达，我们将其命名为“血管抑制素”。“用vasohibin基因转染刘易斯肺癌细胞在体外不影响癌细胞的增殖，但在体内确实抑制了肿瘤生长和肿瘤血管生成。我们建议vasohibin是血管生成的内皮源性负反馈调节剂。
Negative feedback is a crucial physiological regulatory mechanism, but no such regulator of angiogenesis has been established. Here we report a novel angiogenesis inhibitor that is induced in endothelial cells (ECs) by angiogenic factors and inhibits angiogenesis in an autocrine manner. We have performed cDNA microarray analysis to survey VEGF-inducible genes in human ECs. We characterized one such gene, KIAA1036, whose function had been uncharacterized. The recombinant protein inhibited migration, proliferation, and network formation by ECs as well as angiogenesis in vivo. This inhibitory effect was selective to ECs, as the protein did not affect the migration of smooth muscle cells or fibroblasts. Specific elimination of the expression of KIAA1036 in ECs restored their responsiveness to a higher concentration of VEGF. The expression of KIAA1036 was selective to ECs, and hypoxia or TNF-alpha abrogated its inducible expression. As this molecule is preferentially expressed in ECs, we designated it "vasohibin." Transfection of Lewis lung carcinoma cells with the vasohibin gene did not affect the proliferation of cancer cells in vitro, but did inhibit tumor growth and tumor angiogenesis in vivo. We propose vasohibin to be an endothelium-derived negative feedback regulator of angiogenesis.