As embryonic tissues form and grow, the existing vasculature branches out to provide additional oxygen to proliferating cells, and lays the foundation for the intricate vascular network that will support postnatal organ function. As published in the October 15th issue of Genes & Development, Dr. Shima and colleagues now lend valuable insight into the molecular cues that orchestrate this process.
VEGF was previously identified as a potent inducer of angiogenesis in normal physiological contexts (ie., development and wound healing), as well as in the numerous pathological contexts that entail the formation of new vasculature (ie., tumor angiogenesis). There are several different versions of the VEGF protein – called isoforms -- which are generated via alternative RNA splicing from the VEGF gene. The various VEGF isoforms differ in their capacity to bind to the polysaccharide heparin, and thereby in their ability to localize to the extracellular matrix or cell surface.
To investigate the physiological roles of the VEGF isoforms, Dr. Shima and colleagues generated various strains of transgenic mice: One strain solely expressed a soluble (non-heparin-binding) VEGF isoform; another strain solely expressed a heparin-binding isoform. The researchers found that the mice that only expressed soluble VEGF displayed a marked decrease in vessel branching and had abnormally wide microvessels, while the mice that only expressed the heparin-binding VEGF isoform suffered the opposite phenotype: excessive vessel branching and abnormally thin microvasculature. The scientists went on to show that the graded concentration of both soluble and heparin-binding VEGF isoforms is necessary for normal embryonic vessel branching frequency and vessel width.
This work demonstrates that the different VEGF isoforms have different functional roles in embryonic vascular development. Future work will be aimed at delineating the roles of these isoforms in the adult vasculature, and identifying potential therapeutic roles for the isoforms. As the first author, Dr. Christiana Ruhrberg, explains, "Our findings will open up new avenues in the treatment of human disease, because we now know that blood vessel growth might be controlled much more precisely than previously thought through the selective manipulation of the VEGF isoforms."
Journal
Genes & Development