Vascular endothelial growth factor (VEGF) is an important common component in the induction of hippocampal neurogenesis by various means, according to a study published in Nature Genetics by Cao et al. The study also shows that the effect is mediated through one of the receptors for VEGF, the kinase insert domain protein receptor (KDR).

In adult mammals, the subgranular zone of the hippocampus is one of the most active sites of continuing neurogenesis, and the rate of neurogenesis can be increased by various manipulations, including exercise, environmental enrichment and the performance of hippocampus-dependent tasks such as the Morris water maze. Peripheral VEGF has previously been implicated in the ability of exercise to drive neurogenesis, so Cao et al. investigated whether it, or other growth factors, might be produced in the hippocampus of rats and drive neurogenesis induced by hippocampal activity or environmental enrichment.

VEGF was the only growth factor tested that showed an increase in expression in the hippocampus of rats that had either been housed in an enriched environment or trained and tested on the Morris water maze. When the authors used recombinant adeno-associated viral vectors to induce overexpression of VEGF in the rat hippocampus, the rats performed better in learning and memory tests, and also showed increased angiogenesis and neurogenesis in the hippocampus. Overexpression of placental growth factor (PGF) also caused increased angiogenesis, but had no effect on learning or on neurogenesis, supporting the idea that VEGF acts directly on neuronal precursors as well as on vascular endothelial cells. The authors also showed that knocking down expression of VEGF using specific small hairpin RNAs (shRNAs) prevented the induction of neurogenesis by an enriched environment.

VEGF can act through several receptors, including KDR. When overexpression of VEGF in the hippocampus was accompanied by overexpression of a dominant-negative mutant KDR, the effects of VEGF were antagonized. This indicates that KDR is the main mediator of the effects of VEGF on neurogenesis.

These results point towards a common mechanism — involving VEGF signalling through KDR — that links environmental effects, such as learning or enrichment, with the induction of neurogenesis in the hippocampus and with improved cognitive performance.