Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Blood. 2012 Sep 13;120(11):2167-73. doi: 10.1182/blood-2012-03-417824. Epub 2012 Jun 6.
VEGF induces vascular permeability (VP) in ischemic diseases and cancer, leading to many pathophysiological consequences. The molecular mechanisms by which VEGF acts to induce hyperpermeability are poorly understood and in vivo models that easily facilitate real-time, genetic studies of VP do not exist. In the present study, we report a heat-inducible VEGF transgenic zebrafish (Danio rerio) model through which VP can be monitored in real time. Using this approach with morpholino-mediated gene knock-down and knockout mice, we describe a novel role of phospholipase Cβ3 as a negative regulator of VEGF-mediated VP by regulating intracellular Ca2+ release. Our results suggest an important effect of PLCβ3 on VP and provide a new model with which to identify genetic regulators of VP crucial to several disease processes.
VEGF 可诱导缺血性疾病和癌症中的血管通透性 (VP)，导致许多病理生理后果。VEGF 诱导高通透性的分子机制尚不清楚，也不存在易于实时进行 VP 的遗传研究的体内模型。在本研究中，我们通过报告一种热诱导的 VEGF 转基因斑马鱼（Danio rerio）模型，实现了对 VP 的实时监测。使用这种方法结合形态发生素介导的基因敲低和敲除小鼠，我们描述了 PLCβ3 通过调节细胞内 Ca2+释放作为 VEGF 介导的 VP 的负调节剂的新作用。我们的结果表明 PLCβ3 对 VP 有重要影响，并提供了一种新的模型，可用于鉴定对几种疾病过程至关重要的 VP 的遗传调节剂。
