Angiogenesis: An Adaptive Dynamic Biological Patterning Problem

Abstract

Formation of functionally adequate vascular networks by angiogenesis presents a problem in biological patterning. Generated without predetermined spatial patterns, networks must develop hierarchical tree-like structures for efficient convective transport over large distances, combined with dense space-filling meshes for short diffusion distances to every point in the tissue. Moreover, networks must be capable of restructuring in response to changing functional demands without interruption of blood flow. Here, theoretical simulations based on experimental data are used to demonstrate that this patterning problem can be solved through over-abundant stochastic generation of vessels in response to a growth factor generated in hypoxic tissue regions, in parallel with refinement by structural adaptation and pruning. Essential biological mechanisms for generation of adequate and efficient vascular patterns are identified and impairments in vascular properties resulting from defects in these mechanisms are predicted. The results provide a framework for understanding vascular network formation in normal or pathological conditions and for predicting effects of therapies targeting angiogenesis.

Applications of computational models to better understand microvascular remodelling: a focus on biomechanical integration across scales

“…Applications of similar models have also proved useful for investigating network-level haemodynamic changes associated with diabetes, exercise and multiple other scenarios [25][26][27][28][29]. And, more recently, Secomb et al [30] have since extended their classical network-based model to include essential parameters for angiogenesis, allowing for the analysis of endothelial cell sprouting in response to specific growth factors coupled to structural relations and biochemical stimuli. An opportunity to build on this pioneering work is to include local anatomical details that accurately predict vessel-and cell-specific haemodynamics.…”

Biofabrication of Vascular Networks

“…Some computational models incorporate the influence of extravascular matrix dynamics on vessel branching and connections [30,31]. One prediction from these varied models is that new vessel network formation depends on both deterministic and stochastic processes [32]. Still others are using physical laws, such as minimum work/energy rules or fractal dimensionality, to model microvascular branching [33,34].…”

Metabolic Control of Microvascular Networks: Oxygen Sensing and Beyond

“…The metabolic sensor for angiogenesis signaling must be in the tissue and not in the vessel wall or in the RBCs because in the case of insufficient vessel density, vascular pO 2 may be high despite tissue hypoxia [56]. To generate functionally adequate network structures, angiogenesis has to work in concert with the refining processes of vascular diameter remodeling and the pruning of abundant vessels [3]. …”

“…Thus we find…vessels become larger in proportion to the necessity of supply …; the external carotids in the stag, also, when his horns are growing, are much larger than at any other time' [1]. It is now accepted that vessels are dynamic structures, which are controlled in structure and function by hemodynamic and biological signals related to cell metabolism, a process which may be called ‘angioadaptation' including angiogenesis, pruning, remodeling and changes in vascular tone [2,3]. This vascular plasticity stimulates the question as to the mechanisms providing vascular reactions to match substrate supply by the blood to tissue metabolic demand in terminal vascular beds and their functional implications.…”