VEGF and Notch Signaling in Angiogenesis

The vascular system is responsible for providing every cell in vertebrate organisms with a sufficient supply of oxygen and nutrients, allowing waste disposal as well as transmitting immune responses among other functions. Thus, every tissue and organ requires an efficient network of blood vessels, which can be formed de novo (vasculogenesis) or from existing vessels (angiogenesis). The onset of the latter, namely endothelial cell (EC) sprouting, is the focus of this chapter. EC sprouting starts with the differentiation of ECs into guiding tip cells and proliferative stalk cells that form the growing sprout and it ends with the so-called anastomosis, when the sprout fuses with another sprout or existing vessel. The interplay between vascular endothelial growth factor (VEGF) and Notch signaling pathways governs the whole process and directs ECs towards either a tip or stalk cell phenotype. These signaling mechanisms and angiogenesis in general are equally important for wound healing and diseases such as diabetic retinopathy or cancer as tumors cannot exceed a certain size without a proper oxygen supply. Based on this knowledge, VEGF or VEGF receptors (VEGFRs) have become targets of anti-angiogenic tumor therapies. However, their success has turned out to be very limited, and thus, multiple signaling pathways must be aimed at for efficacious treatment. As supported by preclinical data, targeting the VEGF/Notch nexus offers a novel direction for drug development.