Blood vessels are missing branches in mice with no ECM-bound VEGF (right).


Not all isoforms are created equal. New results from Christiana Ruhrberg, David Shima (Cancer Research UK, London, UK), and colleagues reveal that the stickiness of vascular endothelial growth factor (VEGF) can make all the difference between blood vessels growing larger or finding new territory.VEGF initiates the formation and expansion of the vascular system. VEGF isoforms differ in their ability to bind to the extracellular matrix (ECM), but, in vitro, endothelial cell proliferation is stimulated by VEGF regardless of its ECM-binding ability.

In the new study, Shima's group examined mice engineered to make only single VEGF isoforms. These mice reveal that VEGF isoforms have opposing effects on growing vessel networks. Although all forms stimulated cell growth in vivo, mice that expressed only soluble VEGF had expanded microvessels with fewer branches. In contrast, microvessels in mice with only ECM-binding VEGF were narrow and branched excessively.

“Our results indicate that growth is integrated with tissues, because the tissue provides localized cues by depositing VEGF in precise spatial patterns,” says Ruhrberg. The road map is provided by ECM-bound VEGF, which attracted filopodia extending from the tip of a new vessel branch. Soluble VEGF did not remain where it was secreted, but rather traveled further away, thus stimulating expansion of existing vessels from a distance. The authors hope to raise awareness of isoform-specific effects for those considering the use of VEGF for therapy to increase or block angiogenesis. ▪


Ruhrberg, C., et al.
Genes Dev.