title: Endothelial cell adhesion to soluble vascular endothelial growth factor receptor-1 triggers a cell dynamic and angiogenic phenotype.
abstract: The aim of this study was to identify the molecular signals produced in human endothelial cells (ECs) by the interaction of α5β1 integrin with soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) present in the extracellular matrix. We generated a gene expression profile of ECs adhering to sVEGFR-1 or to fibronectin, the classic extracellular matrix ligand for α5β1 integrin or in a nonadhering condition. Several biological pathways were differently modulated, 3 protein kinase C substrates [adducin, myristoylated alanine-rich protein kinase C substrate (MARCKS), and radixin] were differently expressed and phosphorylated when cells adhering to sVEGFR-1 were compared with those adhering to fibronectin. Rac1 activation and Gα13 protein involvement through the interaction with radixin were also detected after attachment to sVEGFR-1, and these responses depended on active VEGFR-2 signaling. On sVEGFR-1, ECs exhibited a motile phenotype that was consistent with the abundant presence of MARCKS, a stabilizer of dynamic adhesions. Moreover, ECs silenced for radixin expression no longer responded to the proangiogenic VEGFR-1-derived peptide 12. We propose that the presence of sVEGFR-1 in the EC microenvironment directs α5β1 integrin signaling to generate a dynamic, motile phenotype. Our findings also provide new insights into the mechanism of action of proangiogenic peptide 12, relevant to a therapeutic perspective.
authors.affiliation: 1Molecular and Cell Biology Laboratory, IDI-IRCCS, via Monti di Creta 104, 00167 Rome, Italy. c.failla@idi.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Orecchia
authors.forename: Amel
authors.initials: A
authors.lastname: Mettouchi
authors.forename: Paolo
authors.initials: P
authors.lastname: Uva
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Simon
authors.forename: Diego
authors.initials: D
authors.lastname: Arcelli
authors.forename: Simona
authors.initials: S
authors.lastname: Avitabile
authors.forename: Gianluca
authors.initials: G
authors.lastname: Ragone
authors.forename: Guerrino
authors.initials: G
authors.lastname: Meneguzzi
authors.forename: Karl H
authors.initials: KH
authors.lastname: Pfenninger
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.forename: Cristina Maria
authors.initials: CM
authors.lastname: Failla
mesh_terms: D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D005353:Fibronectins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: cell migration; integrin α5β1; vessel formation