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.

Highlights

  • Angiogenesis, the formation of new blood vessels from existing vessels, is important in numerous mechanisms in health and disease, including wound healing and tumor development

  • We extend the model with tip and stalk cell differentiation, and systematically vary the parameters of the tip cells to search for properties that make the “tip cells” behave in a biologically realistic manner: i.e., they should move to the sprout tip and affect the overall branching morphology

  • We assumed that a fraction of the cells are “tip cells” and the remaining cells are “stalk cells”, assuming that crossdifferentiation between tip and stalk cells does not occur over the course of the simulation

Read more

Summary

Introduction

Angiogenesis, the formation of new blood vessels from existing vessels, is important in numerous mechanisms in health and disease, including wound healing and tumor development. As a natural response to hypoxia, normal cells and tumor cells secrete a range of growth factors, PLOS ONE | DOI:10.1371/journal.pone.0159478. 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 funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call