Endothelial cell activation in a VEGF-A gradient: relevance to cell fate decisions

Autor: Ann L. Akeson, Diane Wiginton, Amanda Herman, James M. Greenberg
Rok vydání: 2009
Předmět:
Vascular Endothelial Growth Factor A
Gene Expression
Muscle Proteins
Mice
Inbred Strains
Mice
Transgenic
Biology
Cell fate determination
Biochemistry
Article
Mice
Cell Movement
Gene expression
Nuclear Receptor Subfamily 4
Group A
Member 2
Nuclear Receptor Subfamily 4
Group A
Member 1
Animals
Humans
Phosphorylation
Early Growth Response Protein 3
Lung
PI3K/AKT/mTOR pathway
Cells
Cultured
Cell Proliferation
Early Growth Response Protein 1
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Dose-Response Relationship
Drug
Cell growth
Phospholipase C gamma
Intracellular Signaling Peptides and Proteins
Endothelial Cells
Gene Expression Regulation
Developmental
Kinase insert domain receptor
Epithelial Cells
Cell Biology
Embryo
Mammalian
Vascular Endothelial Growth Factor Receptor-2
Cell biology
Endothelial stem cell
DNA-Binding Proteins
Vascular endothelial growth factor A
Kinetics
Tyrosine
Female
Cardiology and Cardiovascular Medicine
Proto-Oncogene Proteins c-akt
Morphogen
Zdroj: Microvascular research. 80(1)
ISSN: 1095-9319
Popis: Distribution of vascular endothelial cell growth factor A (VEGF-A) as a gradient determines microvascular endothelial cell (EC) fate during organogenesis. While much is understood about mechanisms of differential distribution, less is known about how EC perceive and interpret a graded VEGF-A signal to generate positional target gene activation. Using microvascular EC, we analyzed the effect of time and graded VEGF-A input on VEGFR2 autophosphorylation, signal kinase activation and induction of immediate-early genes. The threshold and time to peak activation of VEGFR2 were dependent on signal strength over a 50-fold range in concentration with 3-fold concentration differences readily distinguished. Longer duration of exposure did not compensate for low concentration of VEGF-A, suggesting intensity and duration of signal were not interpreted equivalently. With the same conditions, graded and time-sensitive information was transduced through the PLCgamma/p44/p42MAPK signal pathway but not the parallel AKT pathway. Analysis of MAPK-induced angiogenic immediate-early genes determined that EGR-1, EGR-3, and NR4A1 were dependent on graded input while NR4A2 and DSCR1 were independent with 'switch-like' induction. These data demonstrate rapid, linear integration of VEGF-A levels but independent interpretation of duration of signal and identify potential nodes for segregation of gradient-dependent and -independent responses. These results describe how microvascular EC fate decisions can be determined by comparatively moderate changes in VEGF signal strength, resulting in combinatorial changes in the repertoire of immediate-early genes for transcription effectors.
Databáze: OpenAIRE
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