The FAKs about blood vessel assembly.

The formation of blood vessels during embryonic development is a complex process that requires the coordination of multiple soluble signals, as well as coordinated communication of cells with one another and with their surrounding extracellular matrix (ECM). The process of vessel assembly can be dissected into discernible steps that appear to require unique controls (depicted in the Figure, panel A): induction of mesodermal progenitors to an endothelial fate (differentiation of angioblasts); migration of angioblasts and alignment into a primitive vascular plexus; endothelial tube formation; vascular fusion and plexus remodeling; endothelial cell recruitment of mesenchymal progenitors; and endothelial-induced mural cell differentiation.1 Studies in genetically malleable model systems have enabled the identification of some important soluble effectors, as well as cell junctional and matrix components needed for various stages of vessel formation. However, little is known about how these players are collectively orchestrated to achieve successful assembly of vessel structures. Studies by Ilic and coworkers2 in this issue suggest that focal adhesion kinase (FAK) may function to receive and transduce signals from both growth factors and surrounding ECM to control cellular movement, replication, and perhaps fate during vessel morphogenesis. FAK, a cytoplasmic tyrosine kinase, was initially described to mediate integrin signaling as the binding of ECM to integrins enhances FAK phosphorylation.3,4 FAK, localized to focal adhesions, regulates cell motility by inducing actin polymerization and the turnover of contacts between cells and the ECM.5,6 However, other studies have implicated FAK in the transduction of soluble signals including VEGF-A7–10 and PDGF-B.6 FAK associated with the cytoplasmic domains of growth factor receptors, is phosphorylated in response to ligand binding7,8 and recruits signaling molecules such as Src, PI3K, and Grb2.10–12 The Ilic studies revealed that embryos deficient for FAK5,13 die at E8.5 to 9.5 days with multiple defects, including disrupted vascular development. The process of vessel assembly in these mutants is thought to be arrested after endothelial cell differentiation because CD31 (PECAM)-positive cells were found clustered in FAK / yolk sacs and in embryoid bodies derived from FAK / embryonic stem cells. These cells were unable to form a capillary plexus, and the authors conclude that the primary role of FAK during vessel assembly is to modulate endothelial cell migration and tube formation (also referred to as tubulogenesis). This idea is consistent with the previous finding that cells derived from FAK null embryos exhibit decreased motility and turnover of focal adhesions.5 However, FAK may also play a role in earlier stages of vessel assembly, as discussed in the following sections.