Abstract
Vascular endothelial growth factor (VEGF) is a principal regulator of blood vessel formation and haematopoiesis, but the mechanisms by which VEGF differentially regulates these processes have been elusive. Here we describe a regulatory loop by which VEGF controls survival of haematopoietic stem cells (HSCs). We observed a reduction in survival, colony formation and in vivo repopulation rates of HSCs after ablation of the VEGF gene in mice. Intracellularly acting small-molecule inhibitors of VEGF receptor (VEGFR) tyrosine kinase dramatically reduced colony formation of HSCs, thus mimicking deletion of the VEGF gene. However, blocking VEGF by administering a soluble VEGFR-1, which acts extracellularly, induced only minor effects. These findings support the involvement in HSC survival of a VEGF-dependent internal autocrine loop mechanism (that is, the mechanism is resistant to inhibitors that fail to penetrate the intracellular compartment). Not only ligands selective for VEGF and VEGFR-2 but also VEGFR-1 agonists rescued survival and repopulation of VEGF-deficient HSCs, revealing a function for VEGFR-1 signalling during haematopoiesis.
MeSH terms
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Animals
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Autocrine Communication* / drug effects
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Cell Division / drug effects
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Cell Membrane Permeability
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Cell Survival / drug effects
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Cells, Cultured
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Clone Cells / cytology
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Clone Cells / drug effects
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Clone Cells / metabolism
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Endothelial Growth Factors / antagonists & inhibitors
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Endothelial Growth Factors / genetics
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Endothelial Growth Factors / metabolism*
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Flow Cytometry
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Gene Deletion
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Hematopoiesis / drug effects
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Hematopoietic Stem Cells / cytology*
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism*
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Humans
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Lymphokines / antagonists & inhibitors
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Lymphokines / genetics
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Lymphokines / metabolism*
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Mice
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Mice, Knockout
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Paracrine Communication
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Proto-Oncogene Proteins / agonists
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptor Protein-Tyrosine Kinases / pharmacology
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Receptors, Growth Factor / agonists
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Receptors, Growth Factor / antagonists & inhibitors
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Receptors, Growth Factor / metabolism
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Receptors, Vascular Endothelial Growth Factor
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Reverse Transcriptase Polymerase Chain Reaction
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Solubility
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Transduction, Genetic
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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Lymphokines
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Proto-Oncogene Proteins
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RNA, Messenger
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Receptors, Growth Factor
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Receptor Protein-Tyrosine Kinases
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Receptors, Vascular Endothelial Growth Factor
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Vascular Endothelial Growth Factor Receptor-1