Integrin-dependent and -independent functions of astrocytic fibronectin in retinal angiogenesis
Open accessAbstract
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.
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α5- and β1-integrins and fibronectin are essential for vascular development.
“The α5- and β1-integrins and fibronectin are essential for vascular development (10–13).”
From Targeting β1-integrin inhibits vascular leakage in endotoxemia (2018) · cites this paper as [13]
The α5β1-integrin heterodimer is a major endothelial fibronectin receptor.
“The α5β1-integrin heterodimer is a major endothelial fibronectin receptor.”
From Targeting β1-integrin inhibits vascular leakage in endotoxemia (2018) · cites this paper as [13]
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- Authors
- Stenzel, D., Lundkvist, A., Sauvaget, D., Busse, M., Graupera, M., van der Flier, A., Wijelath, E. S., Murray, J., Sobel, M., Costell, M., Takahashi, S., Fässler, R., Yamaguchi, Y., Gutmann, D. H., Hynes, R. O., & Gerhardt, H.
- Affiliations
- Cancer Research UK (GB)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, E17-227, MIT, Cambridge, MA 02139, USA.
- University of Washington (US)
- Universitat de València (ES)
- Max Planck Institute of Biochemistry (DE)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Washington University in St. Louis (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Gerhardt, Holger
- ORCID
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2011-10-15
- Volume
- 138
- Issue
- 20
- Pages
- 4451-4463
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- PMC
- PMC3177315
- OpenAlex
- W2110014836
- Cited by
- 154
- References
- 47
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 18 · 2023: 6 · 2022: 14 · 2021: 6 · 2020: 7 · 2019: 8 · 2018: 11 · 2017: 9 · 2016: 6 · 2015: 18 · 2014: 11 · 2013: 16 · 2012: 11
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Cancer Research UK
- Lister Institute of Preventive Medicine
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- U.S. Public Health Service (GC11451.126452)
- National Heart, Lung, and Blood Institute (P01HL066105, P01HL 66105, R01HL079182)
- National Institute of General Medical Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- fibronectin, astrocytes, retinal angiogenesis, alpha5beta1 integrin, VEGFR2, PI3K/Akt signaling, endothelial cell migration, heparan sulfate, filopodia, extracellular matrix, RGD motif
- MeSH terms
- Animals, Astrocytes, Cell Movement, Extracellular Matrix, Fibronectins, Heparitin Sulfate, Heparan Sulfate, Mice, Inbred C57BL, Mice, Transgenic, Oligopeptides, Retinal Vessels, Signal Transduction, Integrins, Mice, Knockout, Neovascularization, Physiologic, Phosphatidylinositol 3-Kinases, Integrin alpha5beta1, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Proto-Oncogene Proteins c-akt, Mice, Protein Interaction Domains and Motifs
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