Abstract
Angiogenesis involves the formation of new blood vessels by sprouting or splitting of existing blood vessels. During sprouting, a highly motile type of endothelial cell, called the tip cell, migrates from the blood vessels followed by stalk cells, an endothelial cell type that forms the body of the sprout. To get more insight into how tip cells contribute to angiogenesis, we extended an existing computational model of vascular network formation based on the cellular Potts model with tip and stalk differentiation, without making a priori assumptions about the differences between tip cells and stalk cells. To predict potential differences, we looked for parameter values that make tip cells (a) move to the sprout tip, and (b) change the morphology of the angiogenic networks. The screening predicted that if tip cells respond less effectively to an endothelial chemoattractant than stalk cells, they move to the tips of the sprouts, which impacts the morphology of the networks. A comparison of this model prediction with genes expressed differentially in tip and stalk cells revealed that the endothelial chemoattractant Apelin and its receptor APJ may match the model prediction. To test the model prediction we inhibited Apelin signaling in our model and in an in vitro model of angiogenic sprouting, and found that in both cases inhibition of Apelin or of its receptor APJ reduces sprouting. Based on the prediction of the computational model, we propose that the differential expression of Apelin and APJ yields a "self-generated" gradient mechanisms that accelerates the extension of the sprout.
MeSH terms
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Algorithms
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Animals
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Apelin
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Apelin Receptors
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Blood Vessels / cytology
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Blood Vessels / metabolism
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Blood Vessels / physiology*
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Cell Movement / physiology
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Chemotaxis / physiology
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Computational Biology / methods*
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Computer Simulation
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Endothelial Cells / cytology
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Endothelial Cells / physiology
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Models, Biological
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Neovascularization, Physiologic / physiology*
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RNA Interference
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism
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Signal Transduction / physiology*
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
Substances
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APLN protein, human
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APLNR protein, human
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Apelin
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Apelin Receptors
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Intercellular Signaling Peptides and Proteins
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Receptors, G-Protein-Coupled
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Vascular Endothelial Growth Factor A
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KDR protein, human
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Vascular Endothelial Growth Factor Receptor-2
Grants and funding
This work was financed by the Netherlands Consortium for Systems Biology (NCSB), which is part of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO). The work is part of the research programme “Innovational Research Incentives Scheme Vidi Cross-divisional 2010 ALW” with project number 864.10.009, which is (partly) financed by the Netherlands Organisation for Scientific Research (NWO). The in vitro work was supported by grants from the following Dutch eye funds: Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (ANVVB), Stichting Blinden-Penning, Landelijke Stichting voor Blinden en Slechtzienden (LSBS), Stichting MD fonds (all together cooperated by UitZicht, project # UitZicht2012-17), Nederlandse Vereniging ter Verbetering van het Lot der Blinden, Rotterdamse Stichting Blindenbelangen, Stichting voor Ooglijders and the Stichting Nederlands Oogheelkundig Onderzoek. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.