Speaker
Description
Endothelial cells forming blood vessels display complex collective behavior. During vascular network rearrangement and regression, new capillaries are formed while others regress through cellular rearrangements without relying on cell death or proliferation \cite{franco_dynamic_2015}. Furthermore, endothelial cells in arterioles and venules are polarized in the opposite direction of blood flow, promoting cell movement \cite{barbacena_competition_2022}. However, the biophysical mechanisms driving these rearrangements remain poorly understood.
To investigate these mechanisms, we develop a multi-phase field model in which each cell, the extracellular matrix (ECM), and the vessel lumen are individually modeled using a set of order parameters ${\phi_i}$. A free energy functional $F[{\phi_i}]$ describes the relevant interactions, including cell–cell and cell–ECM adhesion \cite{melo_ecm_2023,nonomura_study_2012}. The time evolution of each order parameter is governed by the Allen–Cahn equation and solved using semi-implicit spectral methods.
Simulation results show that blood flow-induced polarization is essential for obtaining vessel structures with realistic endothelial cell shapes and that lumen stability can be maintained over a range of cell–ECM adhesion values. By incorporating Delta–Notch dynamics, the model reproduces stalk–tip cell patterning in growing sprouts.
Bibliography
@article{franco_dynamic_2015,
title = {Dynamic {Endothelial} {Cell} {Rearrangements} {Drive} {Developmental} {Vessel} {Regression}},
volume = {13},
issn = {1545-7885},
url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002125},
doi = {10.1371/journal.pbio.1002125},
abstract = {Patterning of functional blood vessel networks is achieved by pruning of superfluous connections. The cellular and molecular principles of vessel regression are poorly understood. Here we show that regression is mediated by dynamic and polarized migration of endothelial cells, representing anastomosis in reverse. Establishing and analyzing the first axial polarity map of all endothelial cells in a remodeling vascular network, we propose that balanced movement of cells maintains the primitive plexus under low shear conditions in a metastable dynamic state. We predict that flow-induced polarized migration of endothelial cells breaks symmetry and leads to stabilization of high flow/shear segments and regression of adjacent low flow/shear segments.},
language = {en},
number = {4},
urldate = {2026-03-14},
journal = {PLOS Biology},
author = {Franco, Claudio A. and Jones, Martin L. and Bernabeu, Miguel O. and Geudens, Ilse and Mathivet, Thomas and Rosa, Andre and Lopes, Felicia M. and Lima, Aida P. and Ragab, Anan and Collins, Russell T. and Phng, Li-Kun and Coveney, Peter V. and Gerhardt, Holger},
month = apr,
year = {2015},
keywords = {Endothelial cells, Retina, Cell polarity, Apoptosis, Zebrafish, Blood flow, Cell migration, Shear stresses},
pages = {e1002125},
}
@article{barbacena_competition_2022,
title = {Competition for endothelial cell polarity drives vascular morphogenesis in the mouse retina},
volume = {57},
issn = {15345807},
url = {https://linkinghub.elsevier.com/retrieve/pii/S1534580722006323},
doi = {10.1016/j.devcel.2022.09.002},
language = {en},
number = {19},
urldate = {2026-03-14},
journal = {Developmental Cell},
author = {Barbacena, Pedro and Dominguez-Cejudo, Maria and Fonseca, Catarina G. and Gómez-González, Manuel and Faure, Laura M. and Zarkada, Georgia and Pena, Andreia and Pezzarossa, Anna and Ramalho, Daniela and Giarratano, Ylenia and Ouarné, Marie and Barata, David and Fortunato, Isabela C. and Misikova, Lenka Henao and Mauldin, Ian and Carvalho, Yulia and Trepat, Xavier and Roca-Cusachs, Pere and Eichmann, Anne and Bernabeu, Miguel O. and Franco, Cláudio A.},
month = oct,
year = {2022},
pages = {2321--2333.e9},
}
@article{nonomura_study_2012,
title = {Study on {Multicellular} {Systems} {Using} a {Phase} {Field} {Model}},
volume = {7},
issn = {1932-6203},
url = {https://dx.plos.org/10.1371/journal.pone.0033501},
doi = {10.1371/journal.pone.0033501},
language = {en},
number = {4},
urldate = {2026-03-14},
journal = {PLoS ONE},
author = {Nonomura, Makiko},
editor = {Xu, Ying},
month = apr,
year = {2012},
pages = {e33501},
}
@article{melo_ecm_2023,
title = {The {ECM} and tissue architecture are major determinants of early invasion mediated by {E}-cadherin dysfunction},
volume = {6},
issn = {2399-3642},
url = {https://www.nature.com/articles/s42003-023-05482-x},
doi = {10.1038/s42003-023-05482-x},
abstract = {Abstract
Germline mutations of E-cadherin cause Hereditary Diffuse Gastric Cancer (HDGC), a highly invasive cancer syndrome characterised by the occurrence of diffuse-type gastric carcinoma and lobular breast cancer. In this disease, E-cadherin-defective cells are detected invading the adjacent stroma since very early stages. Although E-cadherin loss is well established as a triggering event, other determinants of the invasive process persist largely unknown. Herein, we develop an experimental strategy that comprises in vitro extrusion assays using E-cadherin mutants associated to HDGC, as well as mathematical models epitomising epithelial dynamics and its interaction with the extracellular matrix (ECM). In vitro, we verify that E-cadherin dysfunctional cells detach from the epithelial monolayer and extrude basally into the ECM. Through phase-field modelling we demonstrate that, aside from loss of cell-cell adhesion, increased ECM attachment further raises basal extrusion efficiency. Importantly, by combining phase-field and vertex model simulations, we show that the cylindrical structure of gastric glands strongly promotes the cell’s invasive ability. Moreover, we validate our findings using a dissipative particle dynamics simulation of epithelial extrusion. Overall, we provide the first evidence that cancer cell invasion is the outcome of defective cell-cell linkages, abnormal interplay with the ECM, and a favourable 3D tissue structure.},
language = {en},
number = {1},
urldate = {2026-03-14},
journal = {Communications Biology},
author = {Melo, Soraia and Guerrero, Pilar and Moreira Soares, Maurício and Bordin, José Rafael and Carneiro, Fátima and Carneiro, Patrícia and Dias, Maria Beatriz and Carvalho, João and Figueiredo, Joana and Seruca, Raquel and Travasso, Rui D. M.},
month = nov,
year = {2023},
pages = {1132},
}
