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dc.contributor.authorPage, Donna J.en_US
dc.contributor.authorThuret, Raphaelen_US
dc.contributor.authorVenkatraman, Lakshmien_US
dc.contributor.authorTakahashi, Tokiharuen_US
dc.contributor.authorBentley, Katieen_US
dc.contributor.authorHerbert, Shane P.en_US
dc.coverage.spatialUnited Statesen_US
dc.date2019-05-15
dc.date.accessioned2020-04-15T15:21:32Z
dc.date.available2020-04-15T15:21:32Z
dc.date.issued2019-06-11
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/31189101
dc.identifier.citationDonna J. Page, Raphael Thuret, Lakshmi Venkatraman, Tokiharu Takahashi, Katie Bentley, Shane P. Herbert. 2019. "Positive Feedback Defines the Timing, Magnitude, and Robustness of Angiogenesis.." Cell Rep, Volume 27, Issue 11, pp. 3139 - 3151.e5. https://doi.org/10.1016/j.celrep.2019.05.052
dc.identifier.issn2211-1247
dc.identifier.urihttps://hdl.handle.net/2144/40179
dc.description.abstractAngiogenesis is driven by the coordinated collective branching of specialized leading "tip" and trailing "stalk" endothelial cells (ECs). While Notch-regulated negative feedback suppresses excessive tip selection, roles for positive feedback in EC identity decisions remain unexplored. Here, by integrating computational modeling with in vivo experimentation, we reveal that positive feedback critically modulates the magnitude, timing, and robustness of angiogenic responses. In silico modeling predicts that positive-feedback-mediated amplification of VEGF signaling generates an ultrasensitive bistable switch that underpins quick and robust tip-stalk decisions. In agreement, we define a positive-feedback loop exhibiting these properties in vivo, whereby Vegf-induced expression of the atypical tetraspanin, tm4sf18, amplifies Vegf signaling to dictate the speed and robustness of EC selection for angiogenesis. Consequently, tm4sf18 mutant zebrafish select fewer motile ECs and exhibit stunted hypocellular vessels with unstable tip identity that is severely perturbed by even subtle Vegfr attenuation. Hence, positive feedback spatiotemporally shapes the angiogenic switch to ultimately modulate vascular network topology.en_US
dc.description.sponsorshipWellcome Trust; 095718/Z/11/Z - Wellcome Trust; BB/N013174/1 - Biotechnology and Biological Sciences Research Council; PG/16/2/31863 - British Heart Foundationen_US
dc.format.extentpp. 3139 - 3151.e5en_US
dc.languageEnglish
dc.language.isoen_US
dc.relation.ispartofCell Reports
dc.rightsCopyright © 2019, Elsevier. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.en_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/.
dc.subjectAngiogenesisen_US
dc.subjectEndothelial cellen_US
dc.subjectLateral inhibitionen_US
dc.subjectPositive feedbacken_US
dc.subjectTetraspaninen_US
dc.subjectTip cellen_US
dc.subjectBiochemistry and cell biologyen_US
dc.titlePositive feedback defines the timing, magnitude, and robustness of angiogenesis.en_US
dc.typeArticleen_US
dc.description.versionPublished versionen_US
dc.identifier.doi10.1016/j.celrep.2019.05.052
pubs.elements-sourcepubmeden_US
pubs.notesEmbargo: No embargoen_US
pubs.organisational-groupBoston Universityen_US
pubs.organisational-groupBoston University, College of Engineeringen_US
pubs.organisational-groupBoston University, College of Engineering, Department of Biomedical Engineeringen_US
pubs.publication-statusPublisheden_US
dc.identifier.mycv477279


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Copyright © 2019, Elsevier. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's license is described as Copyright © 2019, Elsevier. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.