Positive feedback defines the timing, magnitude, and robustness of angiogenesis.
Page, Donna J.
Herbert, Shane P.
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Citation (published version)Donna 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
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 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.
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.