Autocrine fibronectin directs matrix assembly and crosstalk between cell-matrix and cell-cell adhesion in vascular endothelial cells
Autocrine fibronectin directs matrix assembly and crosstalk between cell-matrix and cell-cell adhesion in vascular endothelial cells
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DOI：
10.1242/jcs.073346
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发表时间：
2010-11-15
影响因子：
4
通讯作者：
Van Obberghen-Schilling, Ellen
中科院分区：
文献类型：
--
作者：
Cseh, Botond;Fernandez-Sauze, Samantha;Van Obberghen-Schilling, Ellen
细胞纤维连接蛋白(CFN)突变体含有额外的FN3型重复序列，即额外的B和A结构域，是发育和血管生成过程中新形成血管周围细胞外基质的主要成分。它们的表达是由血管生成刺激诱导的，它们组装成纤维阵列是由细胞在基于α5β1整合素的粘连中产生的张力驱动的。在这里，我们通过异构体选择性RNA干扰检测了CFN变异体在培养的内皮细胞中的作用和功能冗余。我们发现FN的纤维形成是一个细胞自主的过程，在此过程中，细胞FN的碱基定向分泌和组装是紧密耦合的事件，不仅在细胞-基质粘连信号中发挥重要作用，而且在细胞-细胞接触信号中也发挥重要作用。在体外，CFN变异体的沉默不同地影响整合素的使用、细胞的铺展、运动和毛细血管的形态形成。CFN缺陷细胞经历了从基于α5β1到基于αvβ3的黏附转换，伴随着由Src调节的黏附连接的破坏。这些研究表明，自分泌FN在内皮下基质组装和连接完整性中起着至关重要的作用，在血管新生血管重塑过程中提供了对内皮可塑性的时空受限控制。
Cellular fibronectin (cFN) variants harboring extra FN type 3 repeats, namely extra domains B and A, are major constituents of the extracellular matrix around newly forming blood vessels during development and angiogenesis. Their expression is induced by angiogenic stimuli and their assembly into fibrillar arrays is driven by cell-generated tension at alpha 5 beta 1 integrin-based adhesions. Here, we examined the role and functional redundancy of cFN variants in cultured endothelial cells by isoform-selective RNA interference. We show that FN fibrillogenesis is a cell-autonomous process whereby basally directed secretion and assembly of cellular FN are tightly coupled events that play an important role not only in signaling at cell-matrix adhesions but also at cell-cell contacts. Silencing of cFN variants differentially affects integrin usage, cell spreading, motility and capillary morphogenesis in vitro. cFN-deficient cells undergo a switch from alpha 5 beta 1-to alpha v beta 3-based adhesion, accompanied by a Src-regulated disruption of adherens junctions. These studies identify a crucial role for autocrine FN in subendothelial matrix assembly and junctional integrity that provides spatially and temporally restricted control of endothelial plasticity during angiogenic blood vessel remodeling.