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Front. Physiol. | doi: 10.3389/fphys.2017.00960

A network model to explore the effect of the micro-environment on endothelial cell behavior during angiogenesis

 Nathan Weinstein1*,  Luis Mendoza2, Isidoro Gitler1 and  Jaime Klapp3*
  • 1Departamento de Matemáticas, Centro de Investigación y Estudios Avanzados del IPN, Mexico
  • 2Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas de la UNAM, Mexico
  • 3Departamento de Física, National Institute of Nuclear Research (ININ), Mexico

Angiogenesis is an important adaptation mechanism of the blood vessels to the changing requirements of the body during development, aging, and wound healing. Angiogenesis allows existing blood vessels to form new connections or to reabsorb existing ones. Blood vessels are composed of a layer of endothelial cells (ECs) covered by one or more layers of mural cells (smooth muscle cells or pericytes).
We constructed a computational Boolean model of the molecular regulatory network involved in the control of angiogenesis. Our model includes the ANG/TIE, HIF, AMPK/mTOR, VEGF, IGF, FGF, PLC$\gamma$/Calcium, PI3K/AKT, NO, NOTCH, and WNT signaling pathways, as well as the mechanosensory components of the cytoskeleton. The dynamical behavior of our model recovers the patterns of molecular activation observed in Phalanx, Tip, and Stalk ECs. Furthermore, our model is able to describe the modulation of EC behavior due to extracellular micro-environments, as well as the effect due to loss- and gain-of-function mutations. These properties make our model a suitable platform for the understanding of the molecular mechanisms underlying some pathologies. For example, it is possible to follow the changes in the activation patterns caused by mutations that promote Tip EC behavior and inhibit Phalanx EC behavior, that lead to the conditions associated with retinal vascular disorders and tumor vascularization. Moreover, the model describes how mutations that promote Phalanx EC behavior are associated with the development of arteriovenous and venous malformations. These results suggest that the network model that we propose has the potential to be used in the study of how the modulation of the EC extracellular micro-environment may improve the outcome of vascular disease treatments.

Keywords: sprouting angiogenesis, network model, Mechanical Stress, Cell Differentiation, cell polarization, lateral inhibition

Received: 07 Sep 2017; Accepted: 10 Nov 2017.

Edited by:

Matteo Barberis, University of Amsterdam, Netherlands

Reviewed by:

Aleksander S. Popel, Johns Hopkins University, United States
Laurence Calzone, Institut Curie, France  

Copyright: © 2017 Weinstein, Mendoza, Gitler and Klapp. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
PhD. Nathan Weinstein, Centro de Investigación y Estudios Avanzados del IPN, Departamento de Matemáticas, La Marquesa, Ocoyoacac., México, 52740, Estado de México, Mexico, nathan.weinstein4@gmail.com
Prof. Jaime Klapp, National Institute of Nuclear Research (ININ), Departamento de Física, Km. 36.5 Carretera Mexico-Toluca, Ocoyoacac, 52750, Estado de México, Mexico, jaime.klapp@inin.gob.mx