Blood vessel anastomosis is spatially regulated by Flt1 during angiogenesis
Blood vessel anastomosis is spatially regulated by Flt1 during angiogenesis
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DOI：
10.1242/dev.145672
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发表时间：
2017-03-01
期刊：
影响因子：
4.6
通讯作者：
Bautch, Victoria L.
中科院分区：
文献类型：
--
作者：
Nesmith, Jessica E.;Chappell, John C.;Bautch, Victoria L.
血管形成对于脊椎动物发育是必不可少的，并且主要通过血管生成-内皮细胞从预先存在的血管发芽来实现。当新芽形成新的连接时，血管网络就会扩张，这一过程的调控机制尚不清楚。在这里，我们表明，血管吻合的空间调控Flt 1（VEGFR 1），VEGFA受体，作为诱饵受体。在体内，扩张的血管网络有利于与Flt 1突变小鼠内皮细胞的相互作用。体外人内皮细胞的实时成像显示，稳定的连接之前是来自延伸芽的短暂接触，这表明潜在靶位点的采样，Flt 1水平降低，短暂接触减少，VEGFA信号传导增加。Flt 1降低和/或增殖活性升高的靶位点的内皮细胞更可能与传入的芽形成稳定的连接。具有减少的膜定位Flt 1（mFlt 1）但不具有可溶性Flt 1的靶细胞概括了对稳定连接的偏好，表明相对mFlt 1表达在空间上影响稳定连接的选择。因此，芽吻合参数调节VEGFA信号，和稳定的连接在空间上调节内皮细胞的内在调制mFlt 1，这表明新的方法来操纵血管网络的形成。
Blood vessel formation is essential for vertebrate development and is primarily achieved by angiogenesis -endothelial cell sprouting from pre-existing vessels. Vessel networks expand when sprouts form new connections, a process whose regulation is poorly understood. Here, we show that vessel anastomosis is spatially regulated by Flt1 (VEGFR1), a VEGFA receptor that acts as a decoy receptor. In vivo, expanding vessel networks favor interactions with Flt1 mutant mouse endothelial cells. Live imaging in human endothelial cells in vitro revealed that stable connections are preceded by transient contacts from extending sprouts, suggesting sampling of potential target sites, and lowered Flt1 levels reduced transient contacts and increased VEGFA signaling. Endothelial cells at target sites with reduced Flt1 and/or elevated protrusive activity were more likely to form stable connections with incoming sprouts. Target cells with reduced membrane-localized Flt1 (mFlt1), but not soluble Flt1, recapitulated the bias towards stable connections, suggesting that relative mFlt1 expression spatially influences the selection of stable connections. Thus, sprout anastomosis parameters are regulated by VEGFA signaling, and stable connections are spatially regulated by endothelial cell-intrinsic modulation of mFlt1, suggesting new ways to manipulate vessel network formation.