title: Fibronectin fibrillogenesis regulates three-dimensional neovessel formation.
abstract: During vasculogenesis and angiogenesis, endothelial cell responses to growth factors are modulated by the compositional and mechanical properties of a surrounding three-dimensional (3D) extracellular matrix (ECM) that is dominated by either cross-linked fibrin or type I collagen. While 3D-embedded endothelial cells establish adhesive interactions with surrounding ligands to optimally respond to soluble or matrix-bound agonists, the manner in which a randomly ordered ECM with diverse physico-mechanical properties is remodeled to support blood vessel formation has remained undefined. Herein, we demonstrate that endothelial cells initiate neovascularization by unfolding soluble fibronectin (Fn) and depositing a pericellular network of fibrils that serve to support cytoskeletal organization, actomyosin-dependent tension, and the viscoelastic properties of the embedded cells in a 3D-specific fashion. These results advance a new model wherein Fn polymerization serves as a structural scaffolding that displays adhesive ligands on a mechanically ideal substratum for promoting neovessel development.
authors.affiliation: The Division of Molecular Medicine and Genetics, Department of Internal Medicine, The Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhou
authors.forename: R Grant
authors.initials: RG
authors.lastname: Rowe
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Hiraoka
authors.forename: Jerry P
authors.initials: JP
authors.lastname: George
authors.forename: Denis
authors.initials: D
authors.lastname: Wirtz
authors.forename: Deane F
authors.initials: DF
authors.lastname: Mosher
authors.forename: Ismo
authors.initials: I
authors.lastname: Virtanen
authors.forename: Michael A
authors.initials: MA
authors.lastname: Chernousov
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
mesh_terms: D002448:Cell Adhesion; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism*; D005337:Fibrin / Q000378:metabolism; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D018613:Microscopy, Confocal; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009218:Myosins / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D017510:Protein Folding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D016596:Vinculin / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D005353:Fibronectins; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D016596:Vinculin; D049452:Green Fluorescent Proteins; D017228:Hepatocyte Growth Factor; D005337:Fibrin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D009218:Myosins