Disruption of VEGFR signaling leading to developmental defects

BACKGROUND: The cardiovascular system is the first functional organ system to develop in the vertebrate embryo, reflecting its critical role during normal development and pregnancy. Elucidating an AOP for embryonic vascular disruption must consider the stepwise events underlying blood vessel patterning. Vascular development commences in the early embryo with in situ formation of nascent vessels from angioblasts, leading to a primary capillary plexus (vasculogenesis). After the onset of blood circulation, the primary vascular pattern is further expanded as new vessels sprout from pre-existing vessels (angiogenesis). Both processes, vasculogenesis and angiogenesis, are regulated by genetic signals and environmental factors dependent on anatomical region, physiological state, and developmental stage of the embryo. The developing vascular network is further shaped into a hierarchical system of arteries and veins, through progressive effects on blood vessel arborization, branching, and pruning (angio adaptation). These latter influences include hemodynamic forces, regional changes in blood flow, local metabolic demands and growth factor signals. Disruptions in embryonic vascular patterning-adaptation may result in adverse pregnancy outcomes, including birth defects, angiodysplasias and cardiovascular disease, intrauterine growth restriction or prenatal death. Some chemicals may act as potential vascular disrupting compounds (pVDCs) altering the expression, activity or function of molecular signals regulating blood vessel development and remodeling. Critical pathways involve receptor tyrosine kinases (e.g., growth factor-signaling), G-protein coupled receptors (e.g., chemokine signaling), and GPI-anchored receptors (e.g. uPAR system).
DESCRIPTION: This AOP focuses on the regulation and disruption of vasculogenesis angiogenesis during embryonic development via disruption of the VEGF-signaling pathway. VEGFA binding to its cognate receptor (VEGFR2) triggers angiogenic sprouting, growth and fusion during early development, and in flow-sensing adaptation of vascular development during later development. VEGFR2 inhibition, the postulated molecular initiating event (MIE) for this AOP, may be invoked by effects on VEGFA production, mobility, or receptor binding, and by effects on VEGFR2 cellular expression, molecular function or post-receptor signal transduction pathways. Downstream key events (KE) include altered cell fate and behavior of 'endothelial tip cells' (exploratory behavior, cell migration) and endothelial 'stalk cells' (cell proliferation, apoptosis). KE relationships (KERs) leading to vascular insufficiency then involve local interactions with other cell types (stromal cells, macrophages), the extracellular matrix (ECM) and micro-physiology (hemodynamics, metabolism). Adverse outcomes (AO) would ultimately vary by anatomical region, organ system, gestational stage and state of the embryo, fetus or placenta when an MIE is invoked.
RELEVANCE and APPLICATION: Angiogenesis and vascular disruption is a broad concept. The intended use of this AOP in a regulatory context is the predictive toxicology of developmental hazards, especially for integrating data from high-throughput screening (HTS) assays into cell agent-based models for predicting dysmorphogenesis. As part of an integrated assessment of toxicity, this AOP can identify useful information for assessing adverse outcomes relevant to risk assessment and efficient use of resources for validation through predictive models linking developmental toxicity to vascular disruption. AOPbased computer models that simulate vascular development can usher-in new virtual screening techniques to predict what might happen to a developing embryo when exposed to chemicals across different dose-time-stage scenarios, including the range of effects and how cellular injury propagates across development.