title: Endothelial FAK is essential for vascular network stability, cell survival, and lamellipodial formation.
abstract: Morphogenesis of a vascular network requires dynamic vessel growth and regression. To investigate the cellular mechanism underlying this process, we deleted focal adhesion kinase (FAK), a key signaling mediator, in endothelial cells (ECs) using Tie2-Cre mice. Targeted FAK depletion occurred efficiently early in development, where mutants exhibited a distinctive and irregular vasculature, resulting in hemorrhage and lethality between embryonic day (e) 10.5 and 11.5. Capillaries and intercapillary spaces in yolk sacs were dilated before any other detectable abnormalities at e9.5, and explants demonstrate that the defects resulted from the loss of FAK and not from organ failure. Time-lapse microscopy monitoring EC behavior during vascular formation in explants revealed no apparent decrease in proliferation or migration but revealed increases in cell retraction and death leading to reduced vessel growth and increased vessel regression. Consistent with this phenotype, ECs derived from mutant embryos exhibited aberrant lamellipodial extensions, altered actin cytoskeleton, and nonpolarized cell movement. This study reveals that FAK is crucial for vascular morphogenesis and the regulation of EC survival and morphology.
authors.affiliation: The Pacific Vascular Research Laboratory, Division of Vascular Surgery, Department of Surgery, Howard Hughes Medical Institute, San Francisco, CA 94143, USA.
authors.forename: Rickmer
authors.initials: R
authors.lastname: Braren
authors.forename: Huiqing
authors.initials: H
authors.lastname: Hu
authors.forename: Yung Hae
authors.initials: YH
authors.lastname: Kim
authors.forename: Hilary E
authors.initials: HE
authors.lastname: Beggs
authors.forename: Louis F
authors.initials: LF
authors.lastname: Reichardt
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities* / Q000473:pathology; D002196:Capillaries / Q000002:abnormalities / Q000473:pathology; D018376:Cardiovascular Abnormalities / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000098:blood supply / Q000473:pathology; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000172:deficiency* / Q000235:genetics; D019426:Integrases / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D018919:Neovascularization, Physiologic / Q000235:genetics; D011554:Pseudopodia / Q000235:genetics* / Q000473:pathology; D042787:Receptor, TIE-2 / Q000235:genetics
chemical_list: D042787:Receptor, TIE-2; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; C045073:Cre recombinase; D019426:Integrases