Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor.

• Hypoxia as well as global and focal ischemia are strong activators of neurogenesis in the adult mammalian central nervous system. Here we show that the hypoxia-inducible vascular endothelial growth factor (VEGF) and its receptor VEGFR-2/Flk-1 are expressed in clonally-derived adult rat neural stem cells in vitro. VEGF stimulated the expansion of neural stem cells whereas blockade of VEGFR-2/Flk-1-kinase activity reduced neural stem cell expansion. VEGF was also infused into the lateral ventricle to study changes in neurogenesis in the ventricle wall, olfactory bulb and hippocampus. Using a low dose (2.4 ng/d) to avoid endothelial proliferation and changes in vascular permeability, VEGF stimulated adult neurogenesis in vivo. After VEGF infusion, we observed reduced apoptosis but unaltered proliferation suggesting a survival promoting effect of VEGF in neural progenitor cells. Strong expression of VEGFR-2/Flk-1 was detected in the ventricle wall adjacent to the choroid plexus, a site of significant VEGF production, which suggests a paracrine function of endogenous VEGF on neural stem cells in vivo. We propose that VEGF acts as a trophic factor for neural stem cells in vitro and for sustained neurogenesis in the adult nervous system.These findings may have implications for the pathogenesis and therapy of neurodegenerative diseases.

Nyckelord

Animals

Apoptosis

drug effects

Blood-Brain Barrier

drug effects

Brain

drug effects

Cell Survival

drug effects

Female

Immunohistochemistry

In Situ Nick-End Labeling

Injections

Intraventricular

Neurons

drug effects

Rats

Rats

Inbred F344

Reverse Transcriptase Polymerase Chain Reaction

Stem Cells

drug effects

Vascular Endothelial Growth Factor A

pharmacology

Vascular Endothelial Growth Factor Receptor-2

biosynthesis

drug effects

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