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.

Author Summary

The blood vessels provide an efficient system for transport of substances to all parts of the body. They are capable of growing or regressing during development, in response to changing functional needs, and in disease states. This is achieved by structural adaptation, i.e. changes in the diameters and other characteristics of existing vessels, and by angiogenesis, i.e. growth of new blood vessels. Here, we address the question: How do the processes of structural adaptation and angiogenesis lead to the formation of organized vessel networks that can supply the changing needs of the tissue? We carried out theoretical simulations of network growth and adaptation, including vessel blood flows, oxygen transport to tissue, and the generation of a growth factor in low-oxygen regions, which stimulates angiogenesis by sprouting from existing vessels. We showed that the processes of over-abundant random angiogenesis together with structural adaptation including pruning of redundant vessels can generate adequate and efficient vessel networks that are capable of continuously adapting to changing tissue needs. Our work provides insight into the biological mechanisms that are essential for formation and maintenance of functional vessel networks, and may lead to new strategies for controlling blood vessel formation in diseases.