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Key Event Title
Key Event Components
Key Event Overview
AOPs Including This Key Event
Key Event Description
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
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
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.