Fibronectin fibrillogenesis regulates three-dimensional neovessel formation

Xiaoming Zhou; R. Grant Rowe; Nobuaki Hiraoka; Jerry P. George; Denis Wirtz; Deane F. Mosher; Ismo Virtanen; Michael A. Chernousov; Stephen J. Weiss

doi:10.1101/gad.1643308

Fibronectin fibrillogenesis regulates three-dimensional neovessel formation

¹ The Division of Molecular Medicine and Genetics, Department of Internal Medicine, The Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA;
² Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland 21218, USA;
³ Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA;
⁴ Institute of Biomedicine/Anatomy, University of Helsinki, FIN-00014 Finland;
⁵ Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822, USA

↵6 These authors contributed equally to this work.

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.

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