Angiogenic Factors produced by Hypoxic Cells are a leading driver of Anastomoses in Sprouting Angiogenesis–a computational study

Moreira-Soares, Maurício; Coimbra, Rute; Rebelo, Luís; Carvalho, J.; Travasso, Rui D. M.

doi:10.1038/s41598-018-27034-8

Cited by 38 publications

(37 citation statements)

References 96 publications

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“…Angiogenic sprouting has been extensively studied from a theoretical modelling perspective in numerous physiological and pathological contexts, including tumour growth [10,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Many models [18-20, 22, 24-28, 32] fall within the so-called snail-trail paradigm [31].…”

Section: Introductionmentioning

confidence: 99%

A multiscale model of complex endothelial cell dynamics in early angiogenesis

Stepanova

Byrne

Maini

et al. 2020

Preprint

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We introduce a hybrid two-dimensional multiscale model of angiogenesis, the process by which endothelial cells (ECs) migrate from a pre-existing vascular bed in response to local environmental cues and cell-cell interactions, to create a new vascular network. Recent experimental studies have highlighted a central role of cell rearrangements in the formation of angiogenic networks. Our model accounts for this phenomenon via the heterogeneous response of ECs to their microenvironment. These cell rearrangements, in turn, dynamically remodel the local environment. The model reproduces characteristic features of angiogenic sprouting that include branching, chemotactic sensitivity, the brush border effect, and cell mixing. These properties, rather than being hardwired into the model, emerge naturally from the gene expression patterns of individual cells. After calibrating and validating our model against experimental data, we use it to predict how the structure of the vascular network changes as the baseline gene expression levels of the VEGF-Delta-Notch pathway, and the composition of the extracellular environment, vary. In order to investigate the impact of cell rearrangements on the vascular network structure, we introduce the mixing measure, a scalar metric that quantifies cell mixing as the vascular network grows. We calculate the mixing measure for the simulated vascular networks generated by ECs of different lineages (wild type cells and mutant cells with impaired expression of a specific receptor). Our results show that the time evolution of the mixing measure is directly correlated to the generic features of the vascular branching pattern, thus, supporting the hypothesis that cell rearrangements play an essential role in sprouting angiogenesis. Furthermore, we predict that lower cell rearrangement leads to an imbalance between branching and sprout elongation. Since the computation of this statistic requires only individual cell trajectories, it can be computed for networks generated in biological experiments, making it a potential biomarker for pathological angiogenesis. Author summaryAngiogenesis, the process by which new blood vessels are formed by sprouting from the pre-existing vascular bed, plays a key role in both physiological and pathological processes, including tumour growth. The structure of a growing vascular network is determined by the coordinated behaviour of endothelial cells in response to various signalling cues. Recent experimental studies have highlighted the importance of cell rearrangements as a driver for sprout elongation. However, the functional role of this phenomenon remains unclear. We formulate a new multiscale model of angiogenesis which, by accounting explicitly for the complex dynamics of endothelial cells within growing angiogenic sprouts, is able to produce generic features of angiogenic structures (branching, chemotactic sensitivity, cell mixing, etc.) as emergent properties of its dynamics. We validate our model against experimental data and then use it to quantify the pheno...

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Section: Introductionmentioning

confidence: 99%

A multiscale model of complex endothelial cell dynamics in early angiogenesis

Stepanova

Byrne

Maini

et al. 2020

Preprint

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“…VEGF also activates the tip cell phenotype in 24 the vessel endothelial cells (ECs) [17]. The tip cells grow filopodia rich in VEGF receptors, pull the other ECs, open 25 a pathway in the ECM, lead the new sprouts, and migrate in the direction of increasing VEGF concentration [18]. 26 Branching of new sprouts occur as a result of crosstalk between neighboring ECs [19].…”

Section: Introduction 12mentioning

confidence: 99%

“…27 As the new sprouts grow, ECs have to alter their shape to form a lumen connected to the initial vessel that is 28 capable of carrying blood [20][21][22][23][24]. Moreover, in order for the blood to be able to circulate inside the new vessels, the 29 growing sprouts have to merge either with each other or with existing functional mature vessels [25]. The process by 30 which sprouts meet and merge is called anastomosis [25][26][27][28][29].…”

Section: Introduction 12mentioning

confidence: 99%

“…Moreover, in order for the blood to be able to circulate inside the new vessels, the 29 growing sprouts have to merge either with each other or with existing functional mature vessels [25]. The process by 30 which sprouts meet and merge is called anastomosis [25][26][27][28][29]. 31 Nascent sprouts are then covered by pericytes and smooth muscle cells, which provide strength and allow vessel 32 perfusion.…”

Section: Introduction 12mentioning

confidence: 99%

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

Vega

Carretero

Travasso

et al. 2019

Preprint

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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...

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“…It plays a central role in cancer and various ischemic diseases [2,3]. Vascular endothelial growth factor (VEGF) is upregulated by hypoxia during ischemia [4] and is a major stimulatory factor for choroidal neovascularization (CNV) in age-related macular degeneration [5,6] and high myopia [7], as well as retinal neovascularization in diabetic retinopathy [6]. Retinal and choroidal endothelial cells play key roles in the development of retinal and choroidal neovascularization, and subsequent fibrosis.…”

Section: Introductionmentioning

confidence: 99%

The Inhibitory Effects of Gold Nanoparticles on VEGF-A-Induced Cell Migration in Choroid-Retina Endothelial Cells

Chan

Hsiao

et al. 2019

IJMS

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Background: Vascular endothelial growth factor (VEGF) is upregulated by hypoxia and is a crucial stimulator for choroidal neovascularization (CNV) in age-related macular degeneration and pathologic myopia, as well as retinal neovascularization in proliferative diabetic retinopathy. Retinal and choroidal endothelial cells play key roles in the development of retinal and CNV, and subsequent fibrosis. At present, the effects of gold nanoparticles (AuNPs) on the VEGF-induced choroid-retina endothelial (RF/6A) cells are still unknown. In our study, we investigated the effects of AuNPs on RF/6A cell viabilities and cell adhesion to fibronectin, a major ECM protein of fibrovascular membrane. Furthermore, the inhibitory effects of AuNPs on RF/6A cell migration induced by VEGF and its signaling were studied. Methods: The cell viability assay was used to determine the viability of cells treated with AuNPs. The migration of RF/6A cells was assessed by the Transwell migration assay. The cell adhesion to fibronectin was examined by an adhesion assay. The VEGF-induced signaling pathways were determined by western blotting. Results: The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay revealed no cytotoxicity of AuNPs on RF/6A cells. AuNPs inhibited VEGF-induced RF/6A cell migration in a concentration-dependent manner but showed no significant effects on RF/6A cell adhesion to fibronectin. Inhibitory effects of AuNPs on VEGF-induced Akt/eNOS were found. Conclusions: These results suggest that AuNPs are an effective inhibitor of VEGF-induced RF/6A cell migration through the Akt/eNOS pathways, but they have no effects on their cell viabilities and cell adhesion to fibronectin.

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Angiogenic Factors produced by Hypoxic Cells are a leading driver of Anastomoses in Sprouting Angiogenesis–a computational study

Cited by 38 publications

References 96 publications

A multiscale model of complex endothelial cell dynamics in early angiogenesis

A multiscale model of complex endothelial cell dynamics in early angiogenesis

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

The Inhibitory Effects of Gold Nanoparticles on VEGF-A-Induced Cell Migration in Choroid-Retina Endothelial Cells

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