title: Temporal modulation of collective cell behavior controls vascular network topology.
abstract: 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.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, United States.
authors.forename: Esther
authors.initials: E
authors.lastname: Kur
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, United States.
authors.forename: Jiha
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, United States.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Tata
authors.affiliation: Instituto de Física de São Carlos, University of Sao Paulo, Sao Carlos, Brazil.
authors.forename: Cesar H
authors.initials: CH
authors.lastname: Comin
authors.affiliation: Center for Vascular Biology Research, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.
authors.forename: Kyle I
authors.initials: KI
authors.lastname: Harrington
authors.affiliation: Instituto de Física de São Carlos, University of Sao Paulo, Sao Carlos, Brazil.
authors.forename: Luciano da F
authors.initials: Lda F
authors.lastname: Costa
authors.affiliation: Center for Vascular Biology Research, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.
authors.forename: Katie
authors.initials: K
authors.lastname: Bentley
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, United States.
authors.forename: Chenghua
authors.identifier: http://orcid.org/0000-0002-4212-7232
authors.initials: C
authors.lastname: Gu
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003198:Computer Simulation; D042783:Endothelial Cells / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D061848:Optical Imaging; D051880:Receptors, Notch / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: angiogensis; computational biology; computational modeling; delta-notch; developmental biology; mouse; stem cells; systems biology; temporal regulation; tip cell; vascular topology