Abstract
The process of new blood vessel growth (angiogenesis) is highly dynamic, involving complex coordination of multiple cell types. Though the process must carefully unfold over time to generate functional, well-adapted branching networks, we seldom hear about the time-based properties of angiogenesis, despite timing being central to other areas of biology. Here, we present a novel, time-based formulation of endothelial cell behaviour during angiogenesis and discuss a flurry of our recent, integrated in silico/in vivo studies, put in context to the wider literature, which demonstrate that tissue conditions can locally adapt the timing of collective cell behaviours/decisions to grow different vascular network architectures. A growing array of seemingly unrelated ‘temporal regulators’ have recently been uncovered, including tissue derived factors (e.g. semaphorins or the high levels of VEGF found in cancer) and cellular processes (e.g. asymmetric cell division or filopodia extension) that act to alter the speed of cellular decisions to migrate. We will argue that ‘temporal adaptation’ provides a novel account of organ/disease-specific vascular morphology and reveals ‘timing’ as a new target for therapeutics. We therefore propose and explain a conceptual shift towards a ‘temporal adaptation’ perspective in vascular biology, and indeed other areas of biology where timing remains elusive.This article is part of the themed issue ‘Systems morphodynamics: understanding the development of tissue hardware’.
Highlights
Temporal questions are integral to our everyday life: how long will it take? When is the deadline? Am I getting delayed by conversations in the hall? We are ever aware of our ability to be on time or late for events, and the role that local environment may play in affecting our punctuality
This is true in the field of vascular biology and in particular the study of angiogenesis
We propose that filopodia and lamellapodia extension/retraction are a form of just such a sensorimotor coordination or ‘active perception’ by moving the cells’ ‘sensors’ rapidly through the local environment they can better inform the cells on how to respond to the prevailing environmental conditions
Summary
Temporal questions are integral to our everyday life: how long will it take? When is the deadline? Am I getting delayed by conversations in the hall? We are ever aware of our ability to be on time or late for events, and the role that local environment (e.g. obstacles or people talking in hallways) may play in affecting our punctuality. Asymmetric division pre-biases the 7 VEGF arm of the CPG so heavily that the slow selection process through Notch is no longer required, rapidly creating the differences needed to maintain the salt and pepper pattern of migratory cells in this fast moving system This mechanism was found to be conserved in the mesencephalic veins of zebrafish, but only time will tell if it is required or utilized in other organs/organisms. By taking a temporal perspective, we can see there are many alternative ways to alter Notch dynamics and vessel growth by targeting ‘temporal regulators’ of the CPG, opening up a new world of possible strategies to restore the balance, normalizing speed and the asynchronous nature of Notch dynamics required for normal tip cell competition, cell rearrangement, sprouting and vessel diameter This approach was recently explored in an integrated study extending the MSM-CPM model to include metabolic regulation of cell movement. EC metabolism is proposed as a target combined with VEGF inhibitors to best normalize tumour vasculature by altering the temporal dynamics of differential adhesion and cell rearrangement, promoting branching rather than expansion
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