title: Contact-inhibited chemotaxis in de novo and sprouting blood-vessel growth.
abstract: Blood vessels form either when dispersed endothelial cells (the cells lining the inner walls of fully formed blood vessels) organize into a vessel network (vasculogenesis), or by sprouting or splitting of existing blood vessels (angiogenesis). Although they are closely related biologically, no current model explains both phenomena with a single biophysical mechanism. Most computational models describe sprouting at the level of the blood vessel, ignoring how cell behavior drives branch splitting during sprouting. We present a cell-based, Glazier-Graner-Hogeweg model (also called Cellular Potts Model) simulation of the initial patterning before the vascular cords form lumens, based on plausible behaviors of endothelial cells. The endothelial cells secrete a chemoattractant, which attracts other endothelial cells. As in the classic Keller-Segel model, chemotaxis by itself causes cells to aggregate into isolated clusters. However, including experimentally observed VE-cadherin-mediated contact inhibition of chemotaxis in the simulation causes randomly distributed cells to organize into networks and cell aggregates to sprout, reproducing aspects of both de novo and sprouting blood-vessel growth. We discuss two branching instabilities responsible for our results. Cells at the surfaces of cell clusters attempting to migrate to the centers of the clusters produce a buckling instability. In a model variant that eliminates the surface-normal force, a dissipative mechanism drives sprouting, with the secreted chemical acting both as a chemoattractant and as an inhibitor of pseudopod extension. Both mechanisms would also apply if force transmission through the extracellular matrix rather than chemical signaling mediated cell-cell interactions. The branching instabilities responsible for our results, which result from contact inhibition of chemotaxis, are both generic developmental mechanisms and interesting examples of unusual patterning instabilities.
authors.affiliation: VIB Department of Plant Systems Biology, Ghent, Belgium. post@roelandmerks.nl
authors.forename: Roeland M H
authors.initials: RM
authors.lastname: Merks
authors.forename: Erica D
authors.initials: ED
authors.lastname: Perryn
authors.forename: Abbas
authors.initials: A
authors.lastname: Shirinifard
authors.forename: James A
authors.initials: JA
authors.lastname: Glazier
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000254:growth & development*; D002449:Cell Aggregation / Q000502:physiology; D002630:Chemotactic Factors / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology*; D019295:Computational Biology; D003198:Computer Simulation; D003260:Contact Inhibition / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D011554:Pseudopodia / Q000502:physiology
chemical_list: D002630:Chemotactic Factors