Kur, EstherKim, JihaTata, AleksandraComin, Cesar HHarrington, KyleCosta, Luciano da FBentley, KatieGu, Chenghua2016-05-022016Kur, Esther, Jiha Kim, Aleksandra Tata, Cesar H Comin, Kyle I Harrington, Luciano da F Costa, Katie Bentley, and Chenghua Gu. 2016. “Temporal modulation of collective cell behavior controls vascular network topology.” eLife 5 (1): e13212. doi:10.7554/eLife.13212. http://dx.doi.org/10.7554/eLife.13212.2050-084Xhttp://nrs.harvard.edu/urn-3:HUL.InstRepos:26859908Vascular network density determines the amount of oxygen and nutrients delivered to host tissues, but how the vast diversity of densities is generated is unknown. Reiterations of endothelial-tip-cell selection, sprout extension and anastomosis are the basis for vascular network generation, a process governed by the VEGF/Notch feedback loop. Here, we find that temporal regulation of this feedback loop, a previously unexplored dimension, is the key mechanism to determine vascular density. Iterating between computational modeling and in vivo live imaging, we demonstrate that the rate of tip-cell selection determines the length of linear sprout extension at the expense of branching, dictating network density. We provide the first example of a host tissue-derived signal (Semaphorin3E-Plexin-D1) that accelerates tip cell selection rate, yielding a dense network. We propose that temporal regulation of this critical, iterative aspect of network formation could be a general mechanism, and additional temporal regulators may exist to sculpt vascular topology. DOI: http://dx.doi.org/10.7554/eLife.13212.001en-USShort Reportcomputational modelingtip celltemporal regulationvascular topologydelta-notchangiogensisMouseOtherJournal Article2016-05-0210.7554/eLife.13212