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

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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.