A Computational Model Predicting Disruption of Blood Vessel Development
Publication Date
April 04, 2013
Journal
PLOS Computational Biology
Authors
Nicole Kleinstreuer, David Dix, Michael Rountree, Nancy Baker, et al
Volume
9
Issue
4
Pages
e1002996
DOI
https://dx.plos.org/10.1371/journal.pcbi.1002996
Publisher URL
http://journals.plos.org/ploscompbiol/article?id=10.1371%2Fjournal.pcbi.1002996
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/23592958
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616981
Europe PMC
http://europepmc.org/abstract/MED/23592958
Web of Science
000318069800008
Scopus
84876922933
Mendeley
http://www.mendeley.com/research/computational-model-predicting-disruption-blood-vessel-development
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Mendeley | Further Information

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CrossRef

Scopus | Further Information

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Figshare

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  • {"files"=>["https://ndownloader.figshare.com/files/1014816"], "description"=>"<p>Blue diamonds represent half-maximal activity concentrations (AC<sub>50</sub>) with standard error bars.</p>", "links"=>[], "tags"=>["biomap", "measuring", "inhibition", "proliferation", "endothelial", "co-culture", "cells", "peripheral", "mononuclear"], "article_id"=>674989, "categories"=>["Biochemistry", "Genetics"], "users"=>["Nicole Kleinstreuer", "David Dix", "Michael Rountree", "Nancy Baker", "Nisha Sipes", "David Reif", "Richard Spencer", "Thomas Knudsen"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002996.g004", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_5HPP_33_results_in_the_BioMAP_system_measuring_fold_change_levels_for_inhibition_of_proliferation_in_a_endothelial_cells_b_fibroblasts_c_a_co_culture_of_endothelial_cells_and_peripheral_blood_mononuclear_cells_and_d_smooth_muscle_cells_/674989", "title"=>"5HPP-33 results in the BioMAP system measuring fold change levels for inhibition of proliferation in (a) endothelial cells, (b) fibroblasts, (c) a co-culture of endothelial cells and peripheral blood mononuclear cells and (d) smooth muscle cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-04 01:23:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1014831"], "description"=>"<p>Right column gives the cell-type specific “temperature” value, where a higher value corresponds to increased motility <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002996#pcbi.1002996-Merks1\" target=\"_blank\">[16]</a>, <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002996#pcbi.1002996-Merks2\" target=\"_blank\">[25]</a>.</p>", "links"=>[], "tags"=>["energies", "types", "endothelial", "stalk", "mural", "inflammatory", "extracellular", "represents", "higher", "adhesion", "molecules"], "article_id"=>675003, "categories"=>["Biochemistry", "Genetics"], "users"=>["Nicole Kleinstreuer", "David Dix", "Michael Rountree", "Nancy Baker", "Nisha Sipes", "David Reif", "Richard Spencer", "Thomas Knudsen"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002996.t002", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Contact_energies_between_cell_types_EC_t_endothelial_tip_cells_EC_s_endothelial_stalk_cells_MC_mural_cells_IC_inflammatory_cells_ECM_extracellular_matrix_are_shown_where_a_more_negative_number_represents_higher_density_of_cell_adhesion_molecules_and_high/675003", "title"=>"Contact energies between cell types (EC<sub>t</sub>: endothelial tip cells, EC<sub>s</sub>: endothelial stalk cells, MC: mural cells, IC: inflammatory cells, ECM: extracellular matrix) are shown, where a more negative number represents higher density of cell adhesion molecules and higher adhesivity.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-04-04 01:23:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/1014830"], "description"=>"<p>Signaling molecules diffuse uniformly and isotropically. Lattice boundary conditions are periodic.</p>", "links"=>[], "tags"=>["angiogenic", "signals", "represented", "computational", "embryonic", "vascular", "plexus"], "article_id"=>675002, "categories"=>["Biochemistry", "Genetics"], "users"=>["Nicole Kleinstreuer", "David Dix", "Michael Rountree", "Nancy Baker", "Nisha Sipes", "David Reif", "Richard Spencer", "Thomas Knudsen"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002996.t003", "stats"=>{"downloads"=>2, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cell_types_behaviors_and_associated_angiogenic_signals_represented_in_the_computational_model_of_early_embryonic_vascular_plexus_formation_/675002", "title"=>"Cell types, behaviors, and associated angiogenic signals represented in the computational model of early embryonic vascular plexus formation.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-04-04 01:23:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/1014807"], "description"=>"<p>Labels represent simulation time in MCS, where the simulation was run for 10,000 MCS (∼3 hrs). Frames display the progression of interactions between endothelial cells (red), mural cells (green), and inflammatory cells (yellow) as a stable polygonal plexus of endothelial cords emerges. The movie file for the control model is provided as Supplemental <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002996#pcbi.1002996.s009\" target=\"_blank\">Video S1</a>.</p>", "links"=>[], "tags"=>["embryonic", "vascular", "plexus"], "article_id"=>674984, "categories"=>["Biochemistry", "Genetics"], "users"=>["Nicole Kleinstreuer", "David Dix", "Michael Rountree", "Nancy Baker", "Nisha Sipes", "David Reif", "Richard Spencer", "Thomas Knudsen"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002996.g001", "stats"=>{"downloads"=>0, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Control_model_of_early_embryonic_vascular_plexus_formation_/674984", "title"=>"Control model of early embryonic vascular plexus formation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-04 01:23:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/1014821"], "description"=>"<p>Boxes on the left represent molecular initiating events, leading to adverse prenatal outcomes via the associated pathways. The hypothetical linkage between the estrogen receptor (ER) and the angiogenic switch is based on the ToxCast assay results and the known transcriptional relationship between ER and VEGF. In the graphic at right, the colored slices corresponding to each assay are scaled so that more potent (i.e. lower AC<sub>50</sub>) results extend further from the origin.</p>", "links"=>[], "tags"=>["adverse", "pathway", "embryonic", "vascular", "disruption"], "article_id"=>674993, "categories"=>["Biochemistry", "Genetics"], "users"=>["Nicole Kleinstreuer", "David Dix", "Michael Rountree", "Nancy Baker", "Nisha Sipes", "David Reif", "Richard Spencer", "Thomas Knudsen"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002996.g006", "stats"=>{"downloads"=>6, "page_views"=>143, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Proposed_Adverse_Outcome_Pathway_AOP_for_embryonic_vascular_disruption_by_5HPP_33_/674993", "title"=>"Proposed Adverse Outcome Pathway (AOP) for embryonic vascular disruption by 5HPP-33.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-04 01:23:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/1014819"], "description"=>"<p>(A) 5HPP-33 results exhibiting binding of the ER in human (NR_hER), mouse (NR_mERa) and bovine (NR_bER) in NovaScreen system. Blue diamonds represent half-maximal activity concentrations (AC50). (B) 5HPP-33 targeted estrogen receptor alpha transcription factor activity (ERa_TRANS) and the cis-regulatory estrogen response element (ERE_CIS) construct in the Attagene system. Blue diamonds represent half-maximal activity concentrations (AC<sub>50</sub>). Overt cytotoxicity is seen at higher test concentrations; these points are flagged as outliers so that they do not contribute to the reported AC<sub>50</sub> estimate.</p>", "links"=>[], "tags"=>["estrogen", "receptor"], "article_id"=>674992, "categories"=>["Biochemistry", "Genetics"], "users"=>["Nicole Kleinstreuer", "David Dix", "Michael Rountree", "Nancy Baker", "Nisha Sipes", "David Reif", "Richard Spencer", "Thomas Knudsen"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002996.g005", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Modulation_of_the_estrogen_receptor_ER_by_5HPP_33_/674992", "title"=>"Modulation of the estrogen receptor (ER) by 5HPP-33.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-04 01:23:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/1014833"], "description"=>"<p>Diffusion units are pix<sup>2</sup>/s and µm<sup>2</sup>/s, decay units are MCS<sup>−1</sup> and s<sup>−1</sup>, and secretion and uptake units are c.u./pix<sup>2</sup>/s and c.u./µm<sup>2</sup>/s, for parameter and equivalent values, respectively (c.u. is arbitrary concentration units). Parameter values were informed by experimental observations and in most cases estimated to achieve relative steady state concentrations that approximated measured serum levels. References correspond to measured values (diffusion, secretion) or observed behaviors (field coupling, chemotactic strength). EC<sub>t</sub>: endothelial tip cells, EC<sub>s</sub>: endothelial stalk cells, IC: inflammatory cells, MC: mural cells, ECM: extracellular matrix.</p>", "links"=>[], "tags"=>["simulation", "affecting", "fields", "chemotactic"], "article_id"=>675005, "categories"=>["Biochemistry", "Genetics"], "users"=>["Nicole Kleinstreuer", "David Dix", "Michael Rountree", "Nancy Baker", "Nisha Sipes", "David Reif", "Richard Spencer", "Thomas Knudsen"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002996.t004", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dynamic_simulation_parameters_affecting_concentration_fields_and_chemotactic_responses_/675005", "title"=>"Dynamic simulation parameters affecting concentration fields and chemotactic responses.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-04-04 01:23:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/1014814"], "description"=>"<p>(A,B) The hexagonal lacunae formed by the control vascular network model are marked by asterisks, and the arrowheads indicate angiogenic sprouts forming off the nascent vessels. In the computational model, these were seen in response to a local VEGF gradient (green to red color scale indicating low to high concentration). (C,D) Details of EC-tip cell interactions during vascular network formation. Mural cells (green) and inflammatory cells (yellow) interact with endothelial tip cells (dark red) to facilitate bridging between nascent vessel sprouts (arrowheads); endothelial stalk cells (light red) follow and later in time (D) the connection is formed. Macrophage-tip cell bridging (arrow) is an emergent feature of the <i>in silico</i> model and mimics events described during embryogenesis <i>in vivo </i><a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002996#pcbi.1002996-Fantin1\" target=\"_blank\">[31]</a>.</p>", "links"=>[], "tags"=>["emergent", "simulated", "capillary"], "article_id"=>674987, "categories"=>["Biochemistry", "Genetics"], "users"=>["Nicole Kleinstreuer", "David Dix", "Michael Rountree", "Nancy Baker", "Nisha Sipes", "David Reif", "Richard Spencer", "Thomas Knudsen"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002996.g003", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Phenotypic_and_emergent_properties_of_simulated_capillary_plexus_/674987", "title"=>"Phenotypic and emergent properties of simulated capillary plexus.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-04 01:23:07"}
  • {"files"=>["https://ndownloader.figshare.com/files/1014832"], "description"=>"<p>The corresponding gene targets and computational model parameters are shown. SRB represents total protein levels, and is taken as a cytotoxicity measure. AC<sub>50</sub>: half-maximal activity concentration, LEC: Lowest Effective Concentration, E<sub>max</sub>: Maximal response.</p>", "links"=>[], "tags"=>["biomap", "measuring"], "article_id"=>675004, "categories"=>["Biochemistry", "Genetics"], "users"=>["Nicole Kleinstreuer", "David Dix", "Michael Rountree", "Nancy Baker", "Nisha Sipes", "David Reif", "Richard Spencer", "Thomas Knudsen"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002996.t005", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_5HPP_33_results_in_the_BioMAP_system_measuring_fold_change_levels_for_downregulation_upregulation_of_protein_levels_in_human_primary_cells_/675004", "title"=>"5HPP-33 results in the BioMAP system measuring fold change levels for downregulation/upregulation of protein levels in human primary cells.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-04-04 01:23:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/1014829"], "description"=>"<p>The simulation was run in 2D, and 1 pixel is assumed to correspond to 3 µm. 2D “volume” units are pix<sup>2</sup> and µm<sup>2</sup> and “surface area” units are pix and µm, for parameter and equivalent values, respectively. EC<sub>t</sub>: endothelial tip cells, EC<sub>s</sub>: endothelial stalk cells, IC: inflammatory cells, MC: mural cells.</p>", "links"=>[], "tags"=>["parameter", "simulated", "represents", "denotes", "inverse", "compressibility", "membrane"], "article_id"=>675001, "categories"=>["Biochemistry", "Genetics"], "users"=>["Nicole Kleinstreuer", "David Dix", "Michael Rountree", "Nancy Baker", "Nisha Sipes", "David Reif", "Richard Spencer", "Thomas Knudsen"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002996.t001", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Physical_shape_parameter_values_and_equivalent_values_for_each_simulated_cell_type_where_V_t_represents_the_target_volume_V_denotes_the_inverse_compressibility_of_the_cell_S_t_is_the_target_surface_area_and_S_is_the_inverse_membrane_compressibility_/675001", "title"=>"Physical shape parameter values and equivalent values for each simulated cell type, where <i>V<sub>t</sub></i> represents the target volume, <i>λ<sub>V</sub></i> denotes the inverse compressibility of the cell, <i>S<sub>t</sub></i> is the target surface area and <i>λ<sub>S</sub></i> is the inverse membrane compressibility.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-04-04 01:23:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/1014812"], "description"=>"<p>At this stage, there are low levels of protease expression though it can be seen around the sprouting tip cells. The movie file for the control model with overlaid concentration fields is provided as Supplemental <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002996#pcbi.1002996.s010\" target=\"_blank\">Video S2</a>.</p>", "links"=>[], "tags"=>["embryonic", "vascular", "plexus", "cellular", "lattice", "overlaid", "molecular"], "article_id"=>674986, "categories"=>["Biochemistry", "Genetics"], "users"=>["Nicole Kleinstreuer", "David Dix", "Michael Rountree", "Nancy Baker", "Nisha Sipes", "David Reif", "Richard Spencer", "Thomas Knudsen"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002996.g002", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Control_model_of_early_embryonic_vascular_plexus_formation_at_8764_5000_MCS_showing_the_cellular_lattice_and_overlaid_molecular_signaling_concentration_fields_/674986", "title"=>"Control model of early embryonic vascular plexus formation at ∼5000 MCS, showing the cellular lattice and overlaid molecular signaling concentration fields.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-04 01:23:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1014826"], "description"=>"<p>(A) Upper panel shows representative images of AngioTool analysis performed on control, 4.44 µM (5HPP-33 LC) and 40 µM (5HPP-33 HC) simulation outputs. Lower panel shows AngioTool analysis performed on donated experimental images for control, 3 µM 5HPP-33 and 30 µM 5HPP-33 exposure conditions. (B) Graphical representation of explant area, vessels area, vessels percentage area, number of vessel segments, branching index, and lacunarity values for the control model, 4.44 µM (5HPP-33 LC) and 40 µM (5HPP-33 HC). N = 30 simulations for each exposure scenario.</p>", "links"=>[], "tags"=>["5hpp-33", "simulated", "vascular", "plexus"], "article_id"=>674998, "categories"=>["Biochemistry", "Genetics"], "users"=>["Nicole Kleinstreuer", "David Dix", "Michael Rountree", "Nancy Baker", "Nisha Sipes", "David Reif", "Richard Spencer", "Thomas Knudsen"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002996.g008", "stats"=>{"downloads"=>3, "page_views"=>31, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Quantitative_analysis_of_5HPP_33_exposure_on_simulated_vascular_plexus_formation_/674998", "title"=>"Quantitative analysis of 5HPP-33 exposure on simulated vascular plexus formation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-04 01:23:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/1014823"], "description"=>"<p>phase-contrast photomicrographs of human umbilical vein endothelial cells (HUVEC) exposed to 5HPP-33 <i>in vitro</i> (A–C); previously unpublished HUVEC images were graciously donated by Prof. Hashimoto <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002996#pcbi.1002996-Noguchi1\" target=\"_blank\">[56]</a> and show monolayers plated at 5.0×10<sup>5</sup> cells/well grown in DMEM containing angiogenic growth factors (hEGF, VEGF, hFGF-B, and R3-IGF-1) and treated with test compounds (0.5% DMSO vehicle control, 3 µM 5HPP-33, or 30 µM 5HPP-33) for 6 hours. Images are compared to <i>in silico</i> results predicted by the cell-ABM simulation with ToxCast HTS data after 10,000 MCS (D–F). (A,D) Control (DMSO vehicle): demonstrates the polygonal organization of endothelial cells (arrows) <i>in silico</i> (A) or 6 hr HUVEC culture (0.5% DMSO); bar = 100-µm (D). (B,E) Low-concentration 5HPP-33: simulation of ToxCast HTS data for features altered at or below 4.44 µM 5HPP-33 (B); a slightly less connected endothelial network is also observed following exposure to 3 µM 5HPP-33 (E). (C,F) High-concentration 5HPP-33: simulation of ToxCast HTS data for features altered at or below 40 µM 5HPP-33 (C); dispersion and inhibition of vessel formation is also observed following exposure to 30 µM 5HPP-33 (F).</p>", "links"=>[], "tags"=>["5hpp-33"], "article_id"=>674995, "categories"=>["Biochemistry", "Genetics"], "users"=>["Nicole Kleinstreuer", "David Dix", "Michael Rountree", "Nancy Baker", "Nisha Sipes", "David Reif", "Richard Spencer", "Thomas Knudsen"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1002996.g007", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Consequences_of_5HPP_33_exposure_on_vasculogenesis_/674995", "title"=>"Consequences of 5HPP-33 exposure on vasculogenesis:", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-04 01:23:15"}

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Relative Metric

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