Institute for Biochemistry and Biology, Potsdam University, Karl-Liebknecht-Strasse 24-25, Building 26, 14476 Potsdam, Germany; Institute for Molecular Biology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany.
Institut National de la Santé et de la Recherche Médicale (INSERM) U823, Institute Albert Bonniot, 38042 Grenoble, France; Équipes de Recherche Labellisées (ERL) Centre National de la Recherche Scientifique (CNRS) 5284, 38042 Grenoble, France; Université Joseph Fourier, 38042 Grenoble, France.
Dev Cell. 2015 Jan 26;32(2):181-90. doi: 10.1016/j.devcel.2014.12.016.
Mechanotransduction pathways are activated in response to biophysical stimuli during the development or homeostasis of organs and tissues. In zebrafish, the blood-flow-sensitive transcription factor Klf2a promotes VEGF-dependent angiogenesis. However, the means by which the Klf2a mechanotransduction pathway is regulated to prevent continuous angiogenesis remain unknown. Here we report that the upregulation of klf2 mRNA causes enhanced egfl7 expression and angiogenesis signaling, which underlies cardiovascular defects associated with the loss of cerebral cavernous malformation (CCM) proteins in the zebrafish embryo. Using CCM-protein-depleted human umbilical vein endothelial cells, we show that the misexpression of KLF2 mRNA requires the extracellular matrix-binding receptor β1 integrin and occurs in the absence of blood flow. Downregulation of β1 integrin rescues ccm mutant cardiovascular malformations in zebrafish. Our work reveals a β1 integrin-Klf2-Egfl7-signaling pathway that is tightly regulated by CCM proteins. This regulation prevents angiogenic overgrowth and ensures the quiescence of endothelial cells.
机械转导途径在器官和组织的发育或稳态过程中，对生物物理刺激作出反应而被激活。在斑马鱼中，血流敏感的转录因子 Klf2a 促进 VEGF 依赖性血管生成。然而，Klf2a 机械转导途径被调节以防止持续血管生成的方式仍然未知。在这里，我们报告上调 klf2 mRNA 导致增强的 egfl7 表达和血管生成信号，这是与斑马鱼胚胎中脑海绵状血管畸形（CCM）蛋白缺失相关的心血管缺陷的基础。使用 CCM 蛋白耗尽的人脐静脉内皮细胞，我们表明 KLF2 mRNA 的错误表达需要细胞外基质结合受体 β1 整联蛋白，并且发生在没有血流的情况下。下调 β1 整联蛋白可挽救斑马鱼中的 ccm 突变心血管畸形。我们的工作揭示了一个由 CCM 蛋白紧密调节的 β1 整联蛋白-Klf2-Egfl7 信号通路。这种调节可防止血管生成过度生长，并确保内皮细胞的静止。
