Elucidating the role of neuropilin-mediated intercellular adhesion in tissue vascularisation

A large number of conditions such as heart ischemia, diabetic limb neuropathy and several neurodegenerative diseases are characterized by oxygen-deficiency in vital organs. Reagents are continually being developed that modulate the activity of the critical blood vessel growth factor VEGF and its receptors for use in medical therapies aimed at restoring blood supply to such oxygen-deficient organs. However, in several recent mouse models, VEGF delivery resulted in the formation of dangerously tortuous and leaky vessels that were poorly integrated into the surrounding tissue. We therfore need to undestand better how VEGF signals are interpreted by their blood vessel receptors in healthy organs, and how VEGF signals are integrated with other signaling pathway to ensure the coordinated and productive vessel invasion into the oxygen-deficient tissues. The project described in this proposal will determine how the cell surface protein NRP1 functions during blood vessel development. Understanding NRP1 activity is particularly important, because this protein is likely to perform a dual function during blood vessel growth, firstly, as a VEGF receptor, and, secondly, as a mediator of cell-to-cell adhesion between growing vessels and the tissues they invade in response to VEGF signals.

Abnormal vessel regression causes heart, brain and limb ischemia and contributes to a number of other diseases with a significant impact on human health. The stimulation of therapeutic angiogenesis by delivery of angiogenic growth factors is considered a promising treatment for these conditions. However, the modest benefits achieved in recent clinical trials of therapeutic angiogenesis reflect our limited knowledge on the physiological processes that govern the formation of durable blood vessels and their integration into host tissues. The secreted glycoprotein Vascular Endothelial Growth Factor (VEGF) and its receptors KDR, FLT1 and NRP1 (neuropilin 1) are critical factors mediating tissue vascularisation, because they control endothelial differentiation, vessel assembly, vessel sprouting and vessel invasion. We have previously demonstrated the importance of providing a combination of different VEGF isoforms to form functional vascular networks. We now wish to define the essential role of NRP1 in tissue vascularisation. Even though it serves as an isoform-specific VEGF receptor, its precise function has remained elusive and cannot be explained by VEGF binding alone. The project described in this proposal will determine how NRP1?s role as a VEGF receptor is complemented by its role as an intercellular adhesion receptor. This work will benefit our understanding of vascular development, whilst helping to build a conceptual framework for the design of safe angiogenic therapies.