Abstract
Angiogenesis frequently occurs in the context of acute or persistent inflammation. The complex interplay of proinflammatory and proangiogenic cues is only partially understood. Using an 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 proinflammatory cytokine, tumor necrosis factor (TNF), can have both proangiogenic and antiangiogenic 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 proangiogenic to antiangiogenic 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 proinflammatory and antiinflammatory cues, and variable pericyte coverage. The mechanism supports the effect of TNF and pericytes as modulating signaling networks impinging on 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.