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Event: 302

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Production, VEGF-A

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Production, VEGF-A
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Vascular endothelial growth factor A (VEGF-A) is a soluble protein that acts directly on endothelial cells through two receptor tyrosine kinases: VEGFR-1 (Flt-1) and VEGFR-2 (KDR). The former is a decoy receptor that traps VEGF-A into corridors preventing interaction with the active receptor, VEGFR-2. When liganded, VEGFR-2 induces endothelial proliferation, survival, and vascular permeability. The specific MIE considered here is disruption of VEGFR-2 or other transcriptional regulators leading to a change in VEGF-A response. This would include a change in the local production of VEGF-A, an increase in the decoy receptor (VEGFR-1), or a drop in the expression or activity of VEGFR-2. Chemical effects may commence at VEGF receptors (VEGFRs) by ligand production, ligand binding, receptor tyrosine kinase activity, or crosstalk with angiogenic chemokines, cytokines and growth factors.

VEGF-A is locally produced in developing organ systems in the vicinity of target endothelial cells. Hypoxia (and chemical hypoxia) increases VEGF-A production through the HIF-alpha transcription pathway. VEGF-A production is also programmed as a paracrine signal that stimulates endothelial cells in developing tissues, such between astrocyte and endothelial cells during neovascularization of the retina. VEGF transcription is r4egulated by a number of physiological signals including estrogen receptors.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Various examples of bioassays that measure the growth of blood vessels and the effects of specific inhibitors include in vitro assays of endothelial cell migration and proliferation. Some assays test human endothelial cells in primary culture models (e.g., HUVEC), stem-cell derived systems that are capable of de novo assembly into capillary networks, or genetically engineered mouse and zebrafish embryo, and computational models [Mueller et al. 2000; Dorrell et al. 2002; Xia et al. 2009; Chapell et al. 2013; Kleinstreuer et al. 2013]. These assays and models are: (1) fit for the purpose of defining optimal VEGF-A levels for angiogenesis; (2) screening large inventories of small molecules for VEGF-A secretion over a range of chemical concentrations and low oxygen tension; (3) linkage of the MIE with the physiological initiating event; and (4) evaluation of the half-maximal inhibitory concentration (AC50) from a concentration-response curve.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

References

List of the literature that was cited for this KE description. More help

Chappell JC, Taylor SM, Ferrara N, Bautch VL. Local guidance of emerging vessel sprouts requires soluble Flt-1. Developmental cell. 2009;17(3):377-86.

Dorrell MI, Aguilar E, Friedlander M. Retinal vascular development is mediated by endothelial filopodia, a preexisting astrocytic template and specific R-cadherin adhesion. Investigative ophthalmology & visual science. 2002;43(11):3500-10.

Kleinstreuer N, Dix D, Rountree M, Baker N, Sipes N, Reif D, et al. A computational model predicting disruption of blood vessel development. PLoS computational biology. 2013;9(4):e1002996.

Shirinifard A, McCollum CW, Bolin MB, Gustafsson JA, Glazier JA, Clendenon SG. 3D quantitative analyses of angiogenic sprout growth dynamics. Developmental dynamics : an official publication of the American Association of Anatomists. 2013;242(5):518-26.

Xia M, Bi K, Huang R, Cho MH, Sakamuru S, Miller SC, et al. Identification of small molecule compounds that inhibit the HIF-1 signaling pathway. Molecular cancer. 2009;8:117.