The formation of blood and lymphatic vessels is a process of fundamental importance required for the development and maintenance of all organs in higher organisms. In early embryo development, vessels develop from hemangioblasts, a process called vasculogenesis, while later in development and in adult organisms, vessels also derive from preexisting vasculature, a process called angiogenesis. Signaling by vascular endothelial growth factor (VEGF) receptors in endothelial cells establishes the environment required for vessel induction, maturation and maintenance. To build functional vasculature, additional factors such as angiopoietins, TGFβ and PDGF are required giving rise to the complex interplay among different cell types forming mature vasculature.

VEGF receptors are type V receptor tyrosine kinases consisting of an extracellular ligand binding domain, a transmembrane sequence and an intracellular tyrosine kinase domain. VEGF receptors are activated upon ligand binding thereby unleashing the kinase activity of the intracellular kinase domain. Activation of VEGF receptors is followed by engagement of downstream signaling molecules with the intracellular kinase domain of VEGF receptors. Receptor activation results in the activation of a plethora of signaling pathways impinging on the molecular network regulating cell migration, division, and fenestration and ultimately vessel formation (Figure 1). We analyze the mechanism of receptor activation and the signaling pathways activated by VEGF receptors and determine cellular responses in live cells using fluorescence videomicroscopy. Investigating the role of specific VEGF isoforms we found that additional receptors for VEGF, so called co-receptors such as neuropilin-1 and heparan sulfate glycosaminoglycans, modulate receptor output. In this way distinct VEGF isoforms generate diverse signal output. Co-receptors are therefore essential for angiogenic signaling by VEGF receptors.

Structure of VEGF ligands and receptors

Structure of VEGF/VEGFR complex (Use IE 8 from Microsoft, with other brousers use pdf)