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Temporal dynamics of vascular patterning, an integrative approach

Through integrated agent‐based computational modeling with in vitro and in vivo experimentation we are uncovering unexpected temporal dynamic changes during vascular patterning in health and disease. In normal conditions, a VEGF‐Dll4‐Notch signaling feedback loop generates a “salt and pepper pattern” of alternating migratory or inhibited EC phenotypes throughout newly extending vessels, critical to normal branch spacing and elongation. Simulations predicted that if the VEGF levels rise in diseased tissues, such as tumors, then this same pathway can become overloaded, switching ECs to collectively oscillate their Notch signaling, in‐phase with each other, such that large clusters of adjacent cells oscillate between trying to migrate at once or remain still at once, hugely disrupting the branching process. We have now observed first evidence of this temporal patterning switch in vivo and in vitro. We also recently identified that the entire sprouting process is more dynamic than previously thought, with ECs interchanging positions and migratory phenotypes as new vessels form. Predictive simulations led to the discovery that Notch regulates VE‐cadherin turnover, the major adhesion molecule of ECs. Simulations further predict that differential adhesion is required to drive EC intercalation; the clustering of Notch signaling caused by high VEGF levels was found to entirely abrogate intercalation in silico. We subsequently observed first evidence for these predictions in vitro and in vivo with a switch observed in mouse glioblastoma tumor vessels. Together, providing a new explanation for enlarged and poorly branched tumor vessels as a result of a spatiotemporal shift in collective EC signaling and movement dynamics.