Vascular endothelial growth factor receptor Flt-1 negatively regulates developmental blood vessel formation by modulating endothelial cell division
Vascular endothelial growth factor receptor Flt-1 negatively regulates developmental blood vessel formation by modulating endothelial cell division
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DOI：
10.1182/blood.v99.7.2397
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发表时间：
2002-04-01
期刊：
影响因子：
20.3
通讯作者：
Bautch, VL
中科院分区：
文献类型：
--
作者：
Kearney, JB;Ambler, CA;Bautch, VL
缺乏血管内皮生长因子(VEGF)受体FIT-1的小鼠死于血管过度生长，我们感兴趣的是FIT-1通常如何防止这种结果。我们的结果支持这样一个模型，即异常的内皮细胞分裂是导致血管过度生长的细胞机制，他们认为依赖于血管内皮生长因子的内皮细胞分裂通常受到FIT-1的精细调控，以产生血管。FIT-1(-/-)胚胎干细胞培养第8天内皮细胞数量增加2倍，8天前内皮细胞有丝分裂指数显著增加。FIT-1突变胚胎内皮细胞分裂指数也有增加，表明在没有FIT-1的情况下，体内发生了内皮细胞的异常分裂。培养的FIT-1突变的血管系统：被丝裂霉素C处理部分挽救，与突变背景中的细胞分裂缺陷一致。培养分析：在较早的时间点，直到第5天，FIT-1突变培养物增加了β-半乳糖苷酶(+)细胞，这表明FIT-1反应细胞的扩张发生在第4天之后。丝裂霉素C处理阻止了这种早期的扩张，表明血管母细胞和/或内皮细胞的异常分裂是FIT-1突变表型在整个血管发育过程中的特征。与这一模型一致的是，发现在Fit-1突变背景中，血小板和内皮细胞黏附分子(+)和VE-cadherin(+)血管细胞的扩张首先发生在第5天和第6天。综合这些数据，这些数据表明Fit-1在体外和体内都通过控制内皮细胞分裂的速度来调节血管生长。(C)美国血液学学会2002年。
Mice lacking the vascular endothelial growth factor (VEGF) receptor fit-1 die of vascular overgrowth, and we are interested in how fit-1 normally prevents this outcome. Our results support a model whereby aberrant endothelial cell division is the cellular mechanism resulting in vascular overgrowth, and they suggest that VEGF-dependent endothelial cell division is normally finely modulated by fit-1 to produce blood vessels. Fit-1(-/-) embryonic stem cell cultures had a 2-fold increase in endothelial cells by day 8, and the endothelial cell mitotic index was significantly elevated before day 8. Fit-1 mutant embryos also had an increased endothelial cell mitotic index, indicating that aberrant endothelial cell division occurs in vivo in the absence of fit-1. The fit-1 mutant vasculature of the cultures was: partially rescued by mitomycin C treatment, consistent with a cell division defect in the mutant background. Analysis of cultures: at earlier time points showed no significant differences until day 5, when fit-1 mutant cultures had increased beta-galactosidase(+) cells, indicating that the expansion of fit-1 responsive cells occurs after day 4. Mitomycin C treatment blocked this early expansion, suggesting that aberrant division of angioblasts and/or endothelial cells is a hallmark of the fit-1 mutant phenotype throughout vascular development. Consistent with this model is the finding that expansion of platelet and endothelial cell adhesion molecule(+) and VE-cadherin(+) vascular cells in the fit-1 mutant background first,occurs between day 5 and clay 6. Taken together, these data show that fit-1 normally modulates vascular growth by controlling the rate of endothelial cell division both, in vitro and in vivo.(C) 2002 by the American Society of Hematology.