title: Astrocytes spatially restrict VEGF signaling by polarized secretion and incorporation of VEGF into the actively assembling extracellular matrix.
abstract: The spatial organization of vascular endothelial growth factor (VEGF) signaling is a key determinant of vascular patterning during development and tissue repair. How VEGF signaling becomes spatially restricted and the role of VEGF secreting astrocytes in this process remains poorly understood. Using a VEGF-GFP fusion protein and confocal time-lapse microscopy, we observed the intracellular routing, secretion and immobilization of VEGF in scratch-activated living astrocytes. We found VEGF to be directly transported to cell-extracellular matrix attachments where it is incorporated into fibronectin fibrils. VEGF accumulated at β1 integrin containing fibrillar adhesions and was translocated along the cell surface prior to internalization and degradation. We also found that only the astrocyte-derived, matrix-bound, and not soluble VEGF decreases β1 integrin turnover in fibrillar adhesions. We suggest that polarized VEGF release and ECM remodeling by VEGF secreting cells is key to control the local concentration and signaling of VEGF. Our findings highlight the importance of astrocytes in directing VEGF functions and identify these mechanisms as promising target for angiogenic approaches.
authors.affiliation: Department of Neurosciences, University of Geneva, Switzerland.
authors.forename: Kristof
authors.initials: K
authors.lastname: Egervari
authors.affiliation: Department of Neurosciences, University of Geneva, Switzerland.
authors.forename: Gael
authors.initials: G
authors.lastname: Potter
authors.affiliation: Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Guzman-Hernandez
authors.affiliation: Department of Neurosciences, University of Geneva, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Salmon
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Switzerland.
authors.forename: Martinho
authors.initials: M
authors.lastname: Soto-Ribeiro
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Switzerland.
authors.forename: Birgit
authors.initials: B
authors.lastname: Kastberger
authors.affiliation: Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Tamas
authors.initials: T
authors.lastname: Balla
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wehrle-Haller
authors.affiliation: Department of Neurosciences, University of Geneva, Switzerland.
authors.forename: Jozsef Zoltan
authors.initials: JZ
authors.lastname: Kiss
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000648:ultrastructure; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006835:Hydrazones / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism; D038761:Photobleaching; D011691:Puromycin / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D006835:Hydrazones; D019394:Ki-67 Antigen; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins; D011691:Puromycin
keywords: extracellular matrix; fibrillar adhesion; fibronectin; growth factor signaling