Focal adhesion kinase is required for blood vessel morphogenesis.
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.
Ilic
Dusko
D
Department of Stomatology, University of California San Francisco, San Francisco, Calif 94143-0512, USA. ilic@itsa.ucsf.edu
Kovacic
Branka
B
McDonagh
Susan
S
Jin
Fang
F
Baumbusch
Clark
C
Gardner
David G
DG
Damsky
Caroline H
CH
D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities* / Q000201:enzymology* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000098:blood supply / Q000201:enzymology; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009024:Morphogenesis / Q000235:genetics; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D011505:Protein-Tyrosine Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse