Journal of Mathematical Biology
, 58:689
First online:
Angiogenesis and vascular remodelling in normal and cancerous tissues
 Markus R. OwenAffiliated withSchool of Mathematical Sciences, University of Nottingham Email author
 , Tomás AlarcónAffiliated withInstitute for Mathematical Sciences, Imperial College London
 , Philip K. MainiAffiliated withCentre for Mathematical Biology, University of OxfordOxford Centre for Integrative Systems Biology, University of Oxford
 , Helen M. ByrneAffiliated withSchool of Mathematical Sciences, University of Nottingham
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Vascular development and homeostasis are underpinned by two fundamental features: the generation of new vessels to meet the metabolic demands of underperfused regions and the elimination of vessels that do not sustain flow. In this paper we develop the first multiscale model of vascular tissue growth that combines blood flow, angiogenesis, vascular remodelling and the subcellular and tissue scale dynamics of multiple cell populations. Simulations show that vessel pruning, due to low wall shear stress, is highly sensitive to the pressure drop across a vascular network, the degree of pruning increasing as the pressure drop increases. In the model, low tissue oxygen levels alter the internal dynamics of normal cells, causing them to release vascular endothelial growth factor (VEGF), which stimulates angiogenic sprouting. Consequently, the level of blood oxygenation regulates the extent of angiogenesis, with higher oxygenation leading to fewer vessels. Simulations show that network remodelling (and de novo network formation) is best achieved via an appropriate balance between pruning and angiogenesis. An important factor is the strength of endothelial tip cell chemotaxis in response to VEGF. When a cluster of tumour cells is introduced into normal tissue, as the tumour grows hypoxic regions form, producing high levels of VEGF that stimulate angiogenesis and cause the vascular density to exceed that for normal tissue. If the original vessel network is sufficiently sparse then the tumour may remain localised near its parent vessel until new vessels bridge the gap to an adjacent vessel. This can lead to metastable periods, during which the tumour burden is approximately constant, followed by periods of rapid growth.
Keywords
Blood flow Multiscale modelling Tumour angiogenesis Vascular adaptation Vascularisation VEGFMathematics Subject Classification (2000)
9208 92C15 92C17 92C35 62P10 Title
 Angiogenesis and vascular remodelling in normal and cancerous tissues
 Journal

Journal of Mathematical Biology
58:689
 Online Date
 October 2008
 DOI
 10.1007/s002850080213z
 Print ISSN
 03036812
 Online ISSN
 14321416
 Publisher
 SpringerVerlag
 Additional Links
 Topics
 Keywords

 Blood flow
 Multiscale modelling
 Tumour angiogenesis
 Vascular adaptation
 Vascularisation
 VEGF
 9208
 92C15
 92C17
 92C35
 62P10
 Industry Sectors
 Authors

 Markus R. Owen ^{(1)}
 Tomás Alarcón ^{(2)}
 Philip K. Maini ^{(3)} ^{(4)}
 Helen M. Byrne ^{(1)}
 Author Affiliations

 1. School of Mathematical Sciences, University of Nottingham, Nottingham, NG7 2RD, UK
 2. Institute for Mathematical Sciences, Imperial College London, London, SW7 2PG, UK
 3. Centre for Mathematical Biology, University of Oxford, Oxford, OX1 3LB, UK
 4. Oxford Centre for Integrative Systems Biology, University of Oxford, Oxford, OX1 3QU, UK