The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis
The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis
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DOI：
10.1182/blood-2003-07-2315
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发表时间：
2004-06-15
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;Kappas, NC;Bautch, VL
萌发的血管生成是血管形成的关键，但对这一过程的细胞和分子控制知之甚少。我们使用来自干细胞的绿色荧光蛋白(GFP)表达血管的时间推移成像来分析血管发芽形成的动态方面，并确定血管内皮生长因子(VEGF)受体FIT-1如何影响发芽。令人惊讶的是，FIT-1的缺失导致芽的形成和迁移减少，从而导致血管分支减少。这种表型在活体中也可以看到，因为Fit-1(-/-)胚胎有缺陷地从背主动脉发芽。我们以前发现，FIT-1的缺失会增加内皮细胞的分裂速度。然而，分裂的时机与形态发生的影响表明，这些表型没有因果联系，事实上，有丝分裂普遍存在于野生型和FIT-1(-/-)突变维管束的萌发区。相反，通过可溶性FIT-1(-/-)(sFlt-1)转基因挽救分支缺陷支持这样一种模型，即FIT-1通常通过产生SFIT-1来积极调节芽的形成，SFIT-1是一种可溶形式的受体，可以拮抗VEGF信号转导。因此，在血管形成过程中，FIT-1可能会调节生物活性的VEGF-A的精确水平，并可能调节VEGF信号的空间定位，以确保适当的萌芽形成。(C)2004年，由美国血液病学会提供。
Sprouting angiogenesis is critical to blood vessel formation, but the cellular and molecular controls of this process are poorly understood. We used time-lapse imaging of green fluorescent protein (GFP)-expressing vessels derived from stem cells to analyze dynamic aspects of vascular sprout formation and to determine how the vascular endothelial growth factor (VEGF) receptor fit-1 affects sprouting. Surprisingly, loss of fit-1 led to decreased sprout formation and migration, which resulted in reduced vascular branching. This phenotype was also seen in vivo, as fit-1(-/-) embryos had defective sprouting from the dorsal aorta. We previously showed that loss of fit-1 increases the rate of endothelial cell division. However, the timing of division versus morphogenetic effects suggested that these phenotypes were not causally linked, and in fact mitoses were prevalent in the sprout field of both wild-type and fit-1(-/-)mutant vessels. Rather, rescue of the branching defect by a soluble fit-1(-/-) (sflt-1) transgene supports a model whereby fit-1 normally positively regulates sprout formation by production of sfit-1, a soluble form of the receptor that antagonizes VEGF signaling. Thus precise levels of bioactive VEGF-A and perhaps spatial localization of the VEGF signal are likely modulated by fit-1 to ensure proper sprout formation during blood vessel formation. (C) 2004 by The American Society of Hematology.