Zebrafish angiogenesis: a new model for drug screening.
Zebrafish angiogenesis: a new model for drug screening.
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DOI：
10.1023/a:1026598300052
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发表时间：
1999-01-01
期刊：
影响因子：
9.8
通讯作者：
Willett, C E
中科院分区：
文献类型：
--
作者：
Serbedzija, G N;Flynn, E;Willett, C E
血管生成是肿瘤生长所必需的，使得抑制血管形成成为癌症治疗的极好靶点。然而，目前用于血管生成的测定法太复杂而不能用于药物筛选。在这里，我们证明了斑马鱼是一个可行的整体动物模型筛选影响血管形成的小分子。血管图案化在发育中的斑马鱼胚胎中是高度特征性的，并且肠下血管（SIV）可以在显微镜下染色和可视化作为影响血管生成的化合物的初级筛选。直接添加到鱼培养基中的小分子扩散到胚胎中，并诱导可观察到的剂量依赖性效应。为了评估作为模型的斑马鱼，我们使用了两种血管生成抑制剂，SU5416和TNP 470，这两种抑制剂都已在哺乳动物系统中进行了测试。这两种化合物在血管生成开始之前引入斑马鱼胚胎时引起血管形成减少。短时间（1小时）暴露于SU5416足以阻断新的血管生成和血管生成血管的形成。相反，TNP 470需要持续暴露以阻断SIV形成，并且对血管生成性血管形成没有明显影响。为了确定斑马鱼胚胎中的血管是否对血管生成化合物有反应，我们将人VEGF引入胚胎中。注射VEGF引起SIV形成的可观察到的增加。
Angiogenesis is necessary for tumor growth, making inhibition of vessel formation an excellent target for cancer therapy. Current assays for angiogenesis, however, are too complex to be practical for drug screening. Here, we demonstrate that the zebrafish is a viable whole animal model for screening small molecules that affect blood vessel formation. Blood vessel patterning is highly characteristic in the developing zebrafish embryo and the subintestinal vessels (SIVs) can be stained and visualized microscopically as a primary screen for compounds that affect angiogenesis. Small molecules added directly to the fish culture media diffuse into the embryo and induce observable, dose-dependent effects. To evaluate the zebrafish as a model, we used two angiogenesis inhibitors, SU5416 and TNP470, both of which have been tested in mammalian systems. Both compounds caused a reduction in vessel formation when introduced to zebrafish embryos prior to the onset of angiogenesis. Short duration (1 h) exposure of SU5416 was sufficient to block new angiogenic and vasculogenic vessel formation. In contrast, TNP470 required continuous exposure to block SIV formation and had no apparent effect on vasculogenic vessel formation. To ascertain whether blood vessels in the zebrafish embryo respond to angiogenic compounds, we introduced human VEGF into embryos. Injection of VEGF caused an observable increase in SIV formation.