The importance of geometry in the corneal micropocket angiogenesis assay

PLoS Comput Biol. 2018 Mar 9;14(3):e1006049. doi: 10.1371/journal.pcbi.1006049. eCollection 2018 Mar.

Abstract

The corneal micropocket angiogenesis assay is an experimental protocol for studying vessel network formation, or neovascularization, in vivo. The assay is attractive due to the ease with which the developing vessel network can be observed in the same animal over time. Measurements from the assay have been used in combination with mathematical modeling to gain insights into the mechanisms of angiogenesis. While previous modeling studies have adopted planar domains to represent the assay, the hemispherical shape of the cornea and asymmetric positioning of the angiogenic source can be seen to affect vascular patterning in experimental images. As such, we aim to better understand: i) how the geometry of the assay influences vessel network formation and ii) how to relate observations from planar domains to those in the hemispherical cornea. To do so, we develop a three-dimensional, off-lattice mathematical model of neovascularization in the cornea, using a spatially resolved representation of the assay for the first time. Relative to the detailed model, we predict that the adoption of planar geometries has a noticeable impact on vascular patterning, leading to increased vessel 'merging', or anastomosis, in particular when circular geometries are adopted. Significant differences in the dynamics of diffusible aniogenesis simulators are also predicted between different domains. In terms of comparing predictions across domains, the 'distance of the vascular front to the limbus' metric is found to have low sensitivity to domain choice, while metrics such as densities of tip cells and vessels and 'vascularized fraction' are sensitive to domain choice. Given the widespread adoption and attractive simplicity of planar tissue domains, both in silico and in vitro, the differences identified in the present study should prove useful in relating the results of previous and future theoretical studies of neovascularization to in vivo observations in the cornea.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Assay / methods
  • Computer Simulation
  • Cornea / pathology
  • Corneal Neovascularization / classification*
  • Corneal Neovascularization / pathology*
  • Models, Spatial Interaction
  • Models, Theoretical
  • Molecular Dynamics Simulation
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Physiologic / physiology
  • Vascular Endothelial Growth Factor A / physiology

Substances

  • Vascular Endothelial Growth Factor A

Grants and funding

The research leading to these results has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement No 600841. JAG, AJC, HMB and JMPF received this funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.