Notch signaling and taxis mechanisms regulate early stage angiogenesis: A mathematical and computational model

PLoS Comput Biol. 2020 Jan 27;16(1):e1006919. doi: 10.1371/journal.pcbi.1006919. eCollection 2020 Jan.

Abstract

During angiogenesis, new blood vessels sprout and grow from existing ones. This process plays a crucial role in organ development and repair, in wound healing and in numerous pathological processes such as cancer progression or diabetes. Here, we present a mathematical model of early stage angiogenesis that permits exploration of the relative importance of mechanical, chemical and cellular cues. Endothelial cells proliferate and move over an extracellular matrix by following external gradients of Vessel Endothelial Growth Factor, adhesion and stiffness, which are incorporated to a Cellular Potts model with a finite element description of elasticity. The dynamics of Notch signaling involving Delta-4 and Jagged-1 ligands determines tip cell selection and vessel branching. Through their production rates, competing Jagged-Notch and Delta-Notch dynamics determine the influence of lateral inhibition and lateral induction on the selection of cellular phenotypes, branching of blood vessels, anastomosis (fusion of blood vessels) and angiogenesis velocity. Anastomosis may be favored or impeded depending on the mechanical configuration of strain vectors in the ECM near tip cells. Numerical simulations demonstrate that increasing Jagged production results in pathological vasculatures with thinner and more abundant vessels, which can be compensated by augmenting the production of Delta ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Computational Biology
  • Computer Simulation
  • Models, Biological*
  • Neovascularization, Pathologic / physiopathology*
  • Neovascularization, Physiologic / physiology
  • Receptors, Notch / metabolism*
  • Signal Transduction / physiology*
  • Taxis Response / physiology*

Substances

  • Receptors, Notch

Grants and funding

This work has been supported by the FEDER/Ministerio de Ciencia, Innovacion y Universidades -- Agencia Estatal de Investigacion grant MTM2017-84446-C2-2-R (RV, MC and LLB), by the Ministerio de Ciencia, Innovacion y Universidades Salvador de Madariaga grant PRX18/00166 (LLB), by FEDER funds through the Operational Program Competitiveness Factors - COMPETE and by national funds by FCT - Foundation for Science and Technology under the strategic project UID/FIS/04564/2016 and under POCI-01-0145-FEDER-031743 -- PTDC/BIA-CEL/31743/2017 (RDMT), and by the FCT Researcher Program (RDMT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.