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Positive Feedback Defines the Timing, Magnitude, and Robustness of Angiogenesis
Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England;Manchester Metropolitan Univ, Sch Healthcare Sci, Manchester M1 5GD, Lancs, England.
Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Boston Univ, Biomed Engn Dept, 610 Commonwealth Ave, Boston, MA 02215 USA.
Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England.
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2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 27, no 11, p. 3139-3151.e5Article in journal (Refereed) Published
Abstract [en]

Angiogenesis 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 positivefeedback-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 spatiot-emporally shapes the angiogenic switch to ultimately modulate vascular network topology.

Place, publisher, year, edition, pages
2019. Vol. 27, no 11, p. 3139-3151.e5
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Cell Biology Cell and Molecular Biology
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URN: urn:nbn:se:uu:diva-388771DOI: 10.1016/j.celrep.2019.05.052ISI: 000470993200005PubMedID: 31189101OAI: oai:DiVA.org:uu-388771DiVA, id: diva2:1335488
Funder
Knut and Alice Wallenberg FoundationWellcome trust, 095718/Z/11/ZAvailable from: 2019-07-05 Created: 2019-07-05 Last updated: 2019-07-05Bibliographically approved

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