The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching.
The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching.
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DOI：
10.1083/jcb.200709114
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发表时间：
2008-06-02
期刊：
影响因子：
--
通讯作者：
Bautch VL
中科院分区：
文献类型：
--
作者：
Kappas NC;Zeng G;Chappell JC;Kearney JB;Hazarika S;Kallianos KG;Patterson C;Annex BH;Bautch VL
血管形成需要内皮细胞增殖和分支形态发生的综合调节，但这种协调调节是如何实现的还不清楚。Flt-1（血管内皮生长因子[VEGF]受体1）是一种高亲和力的VEGF-A受体，其缺失导致血管过度生长和畸形发生。我们研究了Flt-1同种型转基因拯救胚胎干细胞衍生的Flt-1−/−突变血管的血管发育的能力。可溶性（sFlt-1）和膜栓系（mFlt-1）亚型的内皮细胞增殖得到同等程度的拯救，但只有sFlt-1拯救了血管分支。Flk-1 Tyr-1173磷酸化在flt-1−/−突变血管中增加，并被Flt-1同种型转基因部分挽救。sFlt-1挽救的血管比mFlt-1挽救的血管表现出更多的pFlk异质性水平，并且来自flt-1位点的报告基因表达在发育中的血管中也是异质性的。我们的数据支持sFlt-1蛋白在放大初始表达差异方面比mFlt-1更有效的模型，并且这些放大的差异建立了VEGF-A配体可用性的局部不连续性，这对于适当的血管分支是重要的。
Blood vessel formation requires the integrated regulation of endothelial cell proliferation and branching morphogenesis, but how this coordinated regulation is achieved is not well understood. Flt-1 (vascular endothelial growth factor [VEGF] receptor 1) is a high affinity VEGF-A receptor whose loss leads to vessel overgrowth and dysmorphogenesis. We examined the ability of Flt-1 isoform transgenes to rescue the vascular development of embryonic stem cell–derived flt-1−/− mutant vessels. Endothelial proliferation was equivalently rescued by both soluble (sFlt-1) and membrane-tethered (mFlt-1) isoforms, but only sFlt-1 rescued vessel branching. Flk-1 Tyr-1173 phosphorylation was increased in flt-1−/− mutant vessels and partially rescued by the Flt-1 isoform transgenes. sFlt-1–rescued vessels exhibited more heterogeneous levels of pFlk than did mFlt-1–rescued vessels, and reporter gene expression from the flt-1 locus was also heterogeneous in developing vessels. Our data support a model whereby sFlt-1 protein is more efficient than mFlt-1 at amplifying initial expression differences, and these amplified differences set up local discontinuities in VEGF-A ligand availability that are important for proper vessel branching.
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影响因子：
20.3
作者：
Bautch, VL;Redick, SD;Rapoport, R
通讯作者：
Rapoport, R
影响因子：
1.2
作者：
Hofmann, Jennifer J.;Iruela-Arispe, M. Luisa
通讯作者：
Iruela-Arispe, M. Luisa
影响因子：
2.5
作者：
BREIER, G;CLAUSS, M;RISAU, W
通讯作者：
RISAU, W
影响因子：
4.8
作者：
Neagoe, PE;Lemieux, C;Sirois, MG
通讯作者：
Sirois, MG
影响因子：
20.3
作者：
Kearney, JB;Kappas, NC;Bautch, VL
通讯作者：
Bautch, VL