Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

SVEGFR-1 signaling through Î±5Î²1 integrin

ABSTRACT: Soluble VEGFR-1 (sVEGFR-1) acts both as a decoy receptor for VEGFs and as an extracellular matrix protein for Î±5Î²1 integrin. A sVEGFR-1-derived peptide that interacts with Î±5Î²1 integrin promotes angiogenesis. However, canonical signal downstream integrin activation is not induced, resulting into lack of focal adhesion maturation. We performed a gene expression profile of endothelial cells adhering on sVEGFR-1 compared to that of cells adhering on fibronectin, the principal Î±5Î²1 integrin ligand. Three protein kinase-C substrates, adducin, MARCKS, and radixin were differently modulated. Adducin and MARCKS were less phosphorylated whereas radixin was higher phosphorylated in sVEGFR-1 adhering cells, the latter leading to prolonged small GTPase Rac1 activation and induction of a pathway involving the heterotrimeric G protein Î±13. Altogether, our data indicated endothelial cell acquisition of an highly motile phenotype when adherent on sVEGFR-1. Finally, we indicated radixin as accountable for the angiogenic effect of Î±5Î²1 integrin interaction with sVEGFR-1 that in turn depends on an active VEGF-A/VEGFR-2 signaling. Endothelial cells were let adhere in Petri dishes coated with fibronectin or sVEGFR-1 before RNA extraction and hybridization on Affymetrix microarrays. Endothelial cells plated on BSA-treated Petri dishes were used as non-adhesion control. Each hybridization was performed in triplicate.

ORGANISM(S): Homo sapiens

SUBMITTER: Paolo Uva

PROVIDER: E-GEOD-32560 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Endothelial cell adhesion to soluble vascular endothelial growth factor receptor-1 triggers a cell dynamic and angiogenic phenotype.

Orecchia Angela A Mettouchi Amel A Uva Paolo P Simon Glenn C GC Arcelli Diego D Avitabile Simona S Ragone Gianluca G Meneguzzi Guerrino G Pfenninger Karl H KH Zambruno Giovanna G Failla Cristina Maria CM

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20131030 2

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 subst ...[more]

PMID: 24174428

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Project description:Background and Aims Aging is the primary risk factor for cardiovascular disease (CVD), but the mechanisms underlying age-linked atherosclerosis remain unclear. We previously observed that long-lived vascular matrix proteins can acquire ‘gain-of-function’ isoDGR motifs that might play a role in atherosclerotic pathology. Methods: IsoDGR-specific mAb were generated and used for ELISA-based measurement of motif levels in plasma samples from patients with coronary artery diseases (CAD) and non-CAD controls. Functional consequences of isoDGR accumulation in age-damaged fibronectin were determined by bioassay for capacity to activate monocytes, macrophages, and endothelial cells (signalling activity, pro-inflammatory cytokine expression, and recruitment/adhesion potential). Mice deficient in the isoDGR repair enzyme PCMT1 were used to assess motif distribution and macrophage localisation in vivo. Results: IsoDGR-modified fibronectin and fibrinogen levels in patient plasma were significantly enhanced in CAD and further associated with smoking status. Functional assays demonstrated that isoDGR-modified fibronectin activated both monocytes and macrophages via integrin receptor ‘outside in’ signalling, triggering an ERK:AP-1 cascade and expression of pro-inflammatory cytokines MCP-1 and TNF to drive additional recruitment of circulating leukocytes. IsoDGR-modified fibronectin also induced endothelial cell expression of integrin 1 to further enhance cellular adhesion and matrix deposition. Analysis of murine aortic tissues confirmed accumulation of isoDGR-modified proteins co-localised with CD68+ macrophages in vivo. Conclusions: Age-damaged fibronectin features isoDGR motifs that increase binding to integrins on the surface of monocytes, macrophages, and endothelial cells. Subsequent activation of ‘outside-in’ signalling elicits a range of potent cytokines and chemokines that drive additional leukocyte recruitment to the developing atherosclerotic matrix.

Dataset Information

SVEGFR-1 signaling through Î±5Î²1 integrin

Publications

Endothelial cell adhesion to soluble vascular endothelial growth factor receptor-1 triggers a cell dynamic and angiogenic phenotype.

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