Conformational remodeling of the fibronectin matrix selectively regulates VEGF signaling

Abstract

The fibronectin matrix plays a critical role in the regulation of angiogenesis during development, tissue repair and disease pathogenesis. Earlier work has identified a fibronectin-derived homophilic binding peptide, anastellin, as an effective inhibitor of angiogenesis; however its mechanism of action is not well understood. In the present study, we demonstrate that anastellin selectively inhibits microvessel cell signaling in response to VEGF165 but not VEGF121 by preventing the assembly of the VEGF receptor/Neuropilin-1 complex. Anastellin treatment resulted in the inactivation of α5β1 integrins but was not accompanied by a change in either adhesion complexes or adhesion based signaling. Integrin inactivation was associated with a masking of the fibronectin synergy site within the extracellular matrix, indicating that α5β1 inactivation resulted from a decrease in available ligand. These data demonstrate that anastellin influences the microvessel cell response to growth factors by controlling the repertoire of ligated integrins and point to anastellin as an effective regulator of fibronectin matrix organization. These studies further suggest that homophilic fibronectin binding peptides may have novel applications to the field of tissue regeneration as tools to regulate neovascularization.