Temporal modulation of collective cell behavior controls vascular network topology

• Published in: eLife Vol. 5
• Main Authors: Kur, Esther, Kim, Jiha, Tata, Aleksandra, Comin, Cesar H, Harrington, Kyle I, Costa, Luciano da F, Bentley, Katie, Gu, Chenghua
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 24-02-2016; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Anastomosis; angiogensis; Animals; Cell Proliferation; Computational and Systems Biology; computational modeling; Computer applications; Computer Simulation; delta-notch; Developmental Biology and Stem Cells; Endothelial Cells - physiology; Endothelial growth factors; Feedback; Gene expression; Integrated approach; Mice, Inbred C57BL; Mice, Knockout; Neovascularization, Physiologic; Network topologies; Neural circuitry; Neurosciences; Nutrients; Optical Imaging; Physiological aspects; Receptors, Notch - metabolism; Short Report; Standard deviation; temporal regulation; tip cell; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; vascular topology; computational biology; systems biology; mouse; stem cells; tip cell; temporal regulation; vascular topology; developmental biology; angiogensis; computational modeling; delta-notch
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.13212

Vascular 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.