Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice
Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice
复制标题
DOI：
10.1074/jbc.m314214200
复制
发表时间：
2004-08-13
影响因子：
4.8
通讯作者：
Mori, N
中科院分区：
文献类型：
--
作者：
Furuyama, T;Kitayama, K;Mori, N
FOXO家族成员Foxo1(Fkhr)、Foxo3(Fkhrl1)和FOXO4(AFX)是影响秀丽线虫寿命和能量代谢的daf-16的哺乳动物同源基因。哺乳动物FOXO蛋白在细胞周期停滞、细胞凋亡、抗逆性和能量代谢等方面也发挥着重要作用。在这项研究中，我们建立了FOXO1缺陷小鼠来研究FOXO1的生理作用。Foxo1基因缺陷的小鼠在胚胎第11天左右死亡，原因是鳃弓有缺陷，胚胎和卵黄囊的血管发育明显受损。胚胎干细胞的体外分化表明，来自野生型和Foxo1缺陷胚胎干细胞的内皮细胞能够产生类似数量的克隆，并由一层OP9基质细胞支持。尽管在没有外源性血管内皮生长因子(VEGF)的情况下，两种基因型的内皮细胞集落形态相同，但与野生型内皮细胞相比，Foxo1缺陷的内皮细胞在有外源性VEGF的情况下表现出明显不同的形态反应。这些结果表明，Foxo1对血管内皮细胞对高剂量血管内皮生长因子的正确反应能力是必不可少的，从而在正常的血管发育中发挥关键作用。
Members of the Foxo family, Foxo1 (Fkhr), Foxo3 (Fkhrl1), and Foxo4 (Afx), are mammalian homologs of daf-16, which influences life span and energy metabolism in Caenorhabditis elegans. Mammalian FOXO proteins also play important roles in cell cycle arrest, apoptosis, stress resistance, and energy metabolism. In this study, we generated Foxo1-deficient mice to investigate the physiological role of FOXO1. The Foxo1-deficient mice died around embryonic day 11 because of defects in the branchial arches and remarkably impaired vascular development of embryos and yolk sacs. In vitro differentiation of embryonic stem cells demonstrated that endothelial cells derived from wild-type and Foxo1-deficient embryonic stem cells were able to produce comparable numbers of colonies supported by a layer of OP9 stromal cells. Although the morphology of the endothelial cell colonies was identical in both genotypes in the absence of exogenous vascular endothelial growth factor (VEGF), Foxo1-deficient endothelial cells showed a markedly different morphological response compared with wild-type endothelial cells in the presence of exogenous VEGF. These results suggest that Foxo1 is essential to the ability of endothelial cells to respond properly to a high dose of VEGF, thereby playing a critical role in normal vascular development.