RT Journal Article
SR Electronic
T1 Pericytes enable effective angiogenesis in the presence of pro-inflammatory signals
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 608059
DO 10.1101/608059
A1 Tae-Yun Kang
A1 Federico Bocci
A1 Mohit Kumar Jolly
A1 Herbert Levine
A1 José Nelson Onuchic
A1 Andre Levchenko
YR 2019
UL http://biorxiv.org/content/early/2019/04/13/608059.abstract
AB Angiogenesis frequently occurs in the context of acute or persistent inflammation. The complex interplay of pro-inflammatory and pro-angiogenic cues is only partially understood. Using a new experimental model permitting exposure of developing blood vessel sprouts to multiple combinations of diverse biochemical stimuli and juxtacrine cell interactions, we present evidence that a pro-inflammatory cytokine, tumor necrosis factor (TNF), can have both pro- and anti-angiogenic effects, depending on the dose and the presence of pericytes. In particular, we find that pericytes can rescue and enhance angiogenesis in the presence of otherwise inhibitory high TNF doses. This sharp switch from pro- to anti-angiogenic effect of TNF observed with an escalating dose of this cytokine, as well as the effect of pericytes are explained by a mathematical model trained on the biochemical data. Furthermore, this model was predictive of the effects of diverse combinations of pro-and anti-inflammatory cues, and variable pericyte coverage. The mechanism supports the effect of TNF and pericytes as modulating signaling networks impinging in Notch signaling and specification of the Tip and Stalk phenotypes. This integrative analysis elucidates the plasticity of the angiogenic morphogenesis in the presence of diverse and potentially conflicting cues, with immediate implications for many physiological and pathological settings.