Positive Feedback Defines the Timing, Magnitude, and Robustness of Angiogenesis

TY - JOUR

T1 - Positive Feedback Defines the Timing, Magnitude, and Robustness of Angiogenesis

AU - Page, Donna J.

AU - Thuret, Raphael

AU - Venkatraman, Lakshmi

AU - Takahashi, Tokiharu

AU - Bentley, Katie

AU - Herbert, Shane P.

PY - 2019/6/11

Y1 - 2019/6/11

N2 - 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.

AB - 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.

KW - angiogenesis

KW - endothelial cell

KW - lateral inhibition

KW - positive feedback

KW - tetraspanin

KW - tip cell

UR - http://www.scopus.com/inward/record.url?scp=85066440281&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.05.052

DO - 10.1016/j.celrep.2019.05.052

M3 - Article

AN - SCOPUS:85066440281

SN - 2211-1247

VL - 27

SP - 3139

EP - 3151

JO - Cell Reports

JF - Cell Reports

IS - 11

ER -