Fibronectin fibrillogenesis regulates three-dimensional neovessel formation

• Published in: Genes & development 2008-05, Vol.22 (9), p.1231-1243
• Main Authors: Zhou, Xiaoming, Rowe, R Grant, Hiraoka, Nobuaki, George, Jerry P, Wirtz, Denis, Mosher, Deane F, Virtanen, Ismo, Chernousov, Michael A, Weiss, Stephen J
• Format: Article
• Language: English
• Subjects: Cell Adhesion; Cell Culture Techniques; Cells, Cultured; Collagen Type I - metabolism; Cytoskeleton - metabolism; Cytoskeleton - physiology; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelial Cells - physiology; Extracellular Matrix - chemistry; Extracellular Matrix - metabolism; Fibrin - metabolism; Fibronectins - chemistry; Fibronectins - metabolism; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Hepatocyte Growth Factor - pharmacology; Humans; Immunoblotting; Microscopy, Confocal; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Myosins - metabolism; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - physiology; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Protein Folding; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Research Paper; Transfection; Vascular Endothelial Growth Factor A - pharmacology; Vinculin - genetics; Vinculin - metabolism
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.1643308

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.