Ilic Dusko, Kovacic Branka, McDonagh Susan, Jin Fang, Baumbusch Clark, Gardner David G, Damsky Caroline H
Department of Stomatology, University of California San Francisco, San Francisco, Calif 94143-0512, USA.
Circ Res. 2003 Feb 21;92(3):300-7. doi: 10.1161/01.res.0000055016.36679.23.
The nonreceptor tyrosine kinase focal adhesion kinase (FAK) is a point of convergence for signals from extracellular matrix, soluble factors, and mechanical stimuli. Targeted disruption of the fak gene in mice leads to death at embryonic day 8.5 (E8.5). FAK-/- embryos have severely impaired blood vessel development. Gene expression and in vitro differentiation studies revealed that endothelial cell differentiation was comparable in FAK-/- and wild-type E8.5 embryos. We examined the role of FAK in blood vessel morphogenesis using an in vitro tubulogenesis assay and three different culture systems: FAK+/+ and FAK-/- embryoid bodies, FAK+/+ and FAK-/- endothelial cells, and human umbilical vein endothelial cells expressing antisense FAK, a dominant-negative fragment of FAK, or wild-type FAK. In all of these systems, endothelial cells deficient in FAK expression or function displayed a severely reduced ability to form tubules in Matrigel. These studies demonstrate clearly that the vascular defects in FAK-/- mice result from the inability of FAK-deficient endothelial cells to organize themselves into vascular networks, rather than from defects in tissue-specific differentiation.
非受体酪氨酸激酶粘着斑激酶（FAK）是细胞外基质、可溶性因子和机械刺激信号的汇聚点。在小鼠中靶向破坏fak基因会导致在胚胎第8.5天（E8.5）死亡。FAK基因敲除（FAK-/-）胚胎的血管发育严重受损。基因表达和体外分化研究表明，FAK-/-和野生型E8.5胚胎中的内皮细胞分化情况相当。我们使用体外成管试验和三种不同的培养系统研究了FAK在血管形态发生中的作用：FAK+/+和FAK-/-胚状体、FAK+/+和FAK-/-内皮细胞，以及表达反义FAK、FAK显性负性片段或野生型FAK的人脐静脉内皮细胞。在所有这些系统中，FAK表达或功能缺陷的内皮细胞在基质胶中形成小管的能力严重降低。这些研究清楚地表明，FAK-/-小鼠的血管缺陷是由于FAK缺陷的内皮细胞无法组织成血管网络，而不是由于组织特异性分化缺陷。
