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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Adhesion
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Cell Culture Techniques
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Cells, Cultured
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Collagen Type I / metabolism
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Cytoskeleton / metabolism
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Cytoskeleton / physiology
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Endothelial Cells / cytology
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Endothelial Cells / metabolism
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Endothelial Cells / physiology*
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Extracellular Matrix / chemistry
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Extracellular Matrix / metabolism*
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Fibrin / metabolism
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Fibronectins / chemistry
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Fibronectins / metabolism*
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Hepatocyte Growth Factor / pharmacology
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Humans
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Immunoblotting
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Microscopy, Confocal
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Myosins / metabolism
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / physiology*
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Phosphorylation
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Protein Folding
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Transfection
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Vascular Endothelial Growth Factor A / pharmacology
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Vinculin / genetics
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Vinculin / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Collagen Type I
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Fibronectins
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Recombinant Fusion Proteins
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Vascular Endothelial Growth Factor A
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Vinculin
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Green Fluorescent Proteins
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Hepatocyte Growth Factor
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Fibrin
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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Myosins