Elongation, proliferation & migration differentiate endothelial cell phenotypes and determine capillary sprouting
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BioMed Central
Research article
Open Access
Elongation, proliferation & migration differentiate endothelial cell phenotypes and determine capillary sprouting Amina A Qutub* and Aleksander S Popel Address: 1Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD 21205, USA E-mail: Amina A Qutub* - [email protected]; Aleksander S Popel - [email protected] *Corresponding author
Published: 26 January 2009 BMC Systems Biology 2009, 3:13
Received: 16 September 2008 doi: 10.1186/1752-0509-3-13
Accepted: 26 January 2009
This article is available from: http://www.biomedcentral.com/1752-0509/3/13 © 2009 Qutub and Popel; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background: Angiogenesis, the growth of capillaries from preexisting blood vessels, has been extensively studied experimentally over the past thirty years. Molecular insights from these studies have lead to therapies for cancer, macular degeneration and ischemia. In parallel, mathematical models of angiogenesis have helped characterize a broader view of capillary network formation and have suggested new directions for experimental pursuit. We developed a computational model that bridges the gap between these two perspectives, and addresses a remaining question in angiogenic sprouting: how do the processes of endothelial cell elongation, migration and proliferation contribute to vessel formation? Results: We present a multiscale systems model that closely simulates the mechanisms underlying sprouting at the onset of angiogenesis. Designed by agent-based programming, the model uses logical rules to guide the behavior of individual endothelial cells and segments of cells. The activation, proliferation, and movement of these cells lead to capillary growth in three dimensions. By this means, a novel capillary network emerges out of combinatorially complex interactions of single cells. Rules and parameter ranges are based on literature data on endothelial cell behavior in vitro. The model is designed generally, and will subsequently be applied to represent speciesspecific, tissue-specific in vitro and in vivo conditions. Initial results predict tip cell activation, stalk cell development and sprout formation as a function of local vascular endothelial growth factor concentrations and the Delta-like 4 Notch ligand, as it might occur in a three-dimensional in vitro setting. Results demonstrate the differential effects of ligand concentrations, cell movement and proliferation on sprouting and directional persistence. Conclusion: This systems biology model offers a paradigm closely related to biological phenomena and highlights previously unexplored interactions of cell elongation, migration and proliferation as a function of ligand concentration, giv
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