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. OPEN ACCESS Citation: Vega R, Carretero M, Travasso RDM, Bonilla LL (2020) Notch signaling and taxis mechanisms regulate early stage angiogenesis: A mathematical and computational model. PLoS Comput Biol 16(1): e1006919. https://doi.org/ 10.angiogenesis that is able to explore the role of biochemical signaling and tissue mechanics. We use this model to unravel the regulating role of Jagged, Notch and Delta dynamics in vascular cells. These membrane proteins have an important part in determining the leading cell in each neo-vascular sprout. 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.Notch signaling and taxis mechanisms regulation of early stage angiogenesis PLOS Computational Biology | https://doi.org/10.

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. We present here a mathematical model of early stage angiogenesis that permits to explore 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. Author SummaryAngiogenesis is the process by which new blood vessels grow from existing ones. This process plays a crucial role in 1 organ development, in wound healing and in numerous pathological processes such as cancer growth or in diabetes. 2Angiogenesis is a complex, multi-step and well regulated process where biochemistry and physics are intertwined: 3 with signaling in vessel cells being driven by both chemical and mechanical mechanisms that result in vascular cell 4 movement, deformation and proliferation. Mathematical models have the ability to bring together these mechanisms 5 in order to explore their relative relevance in vessel growth. In this work, we present a mathematical model of early 6 stage angiogenesis that is able to explore the role of biochemical signaling and tissue mechanics. We use this model to 7 unravel the regulating role of Jagged, Notch and Delta dynamics in vascular cells. These membrane proteins have an 8 important part in determining the leading cell in each neo-vascular sprout. Numerical simulations demonstrate that 9 increasing Jagged production results in pathological vasculatures with thinner and more abundant vessels, which can 10 be compensated by augmenting the production of Delta ligands. 101The section Mathematical Model describes the CPM coupled with the Delta-Notch-Jagged dynamics. In the 102 section Results and Discussion, we present the results of the simulation and how Jagged-1 determines sprouting 103 dynamics. Finally, in the last section we draw the conclusions of the manuscript. 104 Mathematical model 105 The mathematical model consists of a CPM in which the dynamics of the Notch signali...

Age-related macular degeneration (AMD) may cause severe loss of vision or blindness, particularly in elderly people. Exudative AMD is characterized by the angiogenesis of blood vessels growing from underneath the macula, crossing the blood–retina barrier (which comprises Bruch’s membrane (BM) and the retinal pigmentation epithelium (RPE)), leaking blood and fluid into the retina and knocking off photoreceptors. Here, we simulate a computational model of angiogenesis from the choroid blood vessels via a cellular Potts model, as well as BM, RPE cells, drusen deposits and photoreceptors. Our results indicate that improving AMD may require fixing the impaired lateral adhesion between RPE cells and with BM, as well as diminishing Vessel Endothelial Growth Factor (VEGF) and Jagged proteins that affect the Notch signaling pathway. Our numerical simulations suggest that anti-VEGF and anti-Jagged therapies could temporarily halt exudative AMD while addressing impaired cellular adhesion, which could be more effective over a longer time-span.

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