Title: Integrin-dependent and -independent functions of astrocytic fibronectin in retinal angiogenesis
Authors: Stenzel, Denise ×
Lundkvist, Andrea
Sauvaget, Dominique
Busse, Marta
Graupera, Mariona
van der Flier, Arjan
Wijelath, Errol S
Murray, Jacqueline
Sobel, Michael
Costell, Mercedes
Takahashi, Seiichiro
Fässler, Reinhard
Yamaguchi, Yu
Gutmann, David H
Hynes, Richard O
Gerhardt, Holger #
Issue Date: Oct-2011
Publisher: Company of Biologists
Series Title: Development vol:138 issue:20 pages:4451-63
Abstract: Fibronectin (FN) is a major component of the extracellular matrix and functions in cell adhesion, cell spreading and cell migration. In the retina, FN is transiently expressed and assembled on astrocytes (ACs), which guide sprouting tip cells and deposit a provisional matrix for sprouting angiogenesis. The precise function of FN in retinal angiogenesis is largely unknown. Using genetic tools, we show that astrocytes are the major source of cellular FN during angiogenesis in the mouse retina. Deletion of astrocytic FN reduces radial endothelial migration during vascular plexus formation in a gene dose-dependent manner. This effect correlates with reduced VEGF receptor 2 and PI3K/AKT signalling, and can be mimicked by selectively inhibiting VEGF-A binding to FN through intraocular injection of blocking peptides. By contrast, AC-specific replacement of the integrin-binding RGD sequence with FN-RGE or endothelial deletion of itga5 shows little effect on migration and PI3K/AKT signalling, but impairs filopodial alignment along AC processes, suggesting that FN-integrin α5β1 interaction is involved in filopodial adhesion to the astrocytic matrix. AC FN shares its VEGF-binding function and cell-surface distribution with heparan-sulfate (HS), and genetic deletion of both FN and HS together greatly enhances the migration defect, indicating a synergistic function of FN and HS in VEGF binding. We propose that in vivo the VEGF-binding properties of FN and HS promote directional tip cell migration, whereas FN integrin-binding functions to support filopodia adhesion to the astrocytic migration template.
ISSN: 0950-1991
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Vascular Patterning Laboratory (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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