title: A cellular Potts model analyzing differentiated cell behavior during in vivo vascularization of a hypoxic tissue.
abstract: Angiogenesis, the formation of new blood vessel networks from existing capillary or post-capillary venules, is an intrinsically multiscale process occurring in several physio-pathological conditions. In particular, hypoxic tissue cells activate downstream cascades culminating in the secretion of a wide range of angiogenic factors, including VEGF isoforms. Such diffusive chemicals activate the endothelial cells (ECs) forming the external walls of the nearby vessels that chemotactically migrate toward the hypoxic areas of the tissue as multicellular sprouts. A functional network eventually emerges by further branching and anastomosis processes. We here propose a CPM-based approach reproducing selected features of the angiogenic progression necessary for the reoxygenation of a hypoxic tissue. Our model is able to span the different scale involved in the angiogenic progression as it incorporates reaction-diffusion equations for the description of the evolution of microenvironmental variables in a discrete mesoscopic cellular Potts model (CPM) that reproduces the dynamics of the vascular cells. A key feature of this work is the explicit phenotypic differentiation of the ECs themselves, distinguished in quiescent, stalk and tip. The simulation results allow identifying a set of key mechanisms underlying tissue vascularization. Further, we provide evidence that the nascent pattern is characterized by precise topological properties. Finally, we link abnormal sprouting angiogenesis with alteration in selected cell behavior.
authors.affiliation: Department of Mathematics, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino, Italy. Electronic address: marcosci1@alice.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Scianna
authors.affiliation: Department of Life Sciences and Systems Biology, University of Torino, Via Accademia Albertina 13, 10123 Torino, Italy. Electronic address: eleonora.bassino@unito.it.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Bassino
authors.affiliation: Department of Life Sciences and Systems Biology, University of Torino, Via Accademia Albertina 13, 10123 Torino, Italy. Electronic address: luca.munaron@unito.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Munaron
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology; D008955:Models, Cardiovascular; D018919:Neovascularization, Physiologic; D020033:Protein Isoforms / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Angiogenesis; Capillary network; Delta-notch signaling; Multiscale model; Oxygenation of hypoxic tissues