Abstract
Vascular development is a complex process regulated by dynamic biological networks that vary in topology and state across different tissues and developmental stages. Signals regulating de novo blood vessel formation (vasculogenesis) and remodeling (angiogenesis) come from a variety of biological pathways linked to endothelial cell (EC) behavior, extracellular matrix (ECM) remodeling and the local generation of chemokines and growth factors. Simulating these interactions at a systems level requires sufficient biological detail about the relevant molecular pathways and associated cellular behaviors, and tractable computational models that offset mathematical and biological complexity. Here, we describe a novel multicellular agent-based model of vasculogenesis using the CompuCell3D (http://www.compucell3d.org/) modeling environment supplemented with semi-automatic knowledgebase creation. The model incorporates vascular endothelial growth factor signals, pro- and anti-angiogenic inflammatory chemokine signals, and the plasminogen activating system of enzymes and proteases linked to ECM interactions, to simulate nascent EC organization, growth and remodeling. The model was shown to recapitulate stereotypical capillary plexus formation and structural emergence of non-coded cellular behaviors, such as a heterologous bridging phenomenon linking endothelial tip cells together during formation of polygonal endothelial cords. Molecular targets in the computational model were mapped to signatures of vascular disruption derived from in vitro chemical profiling using the EPA's ToxCast high-throughput screening (HTS) dataset. Simulating the HTS data with the cell-agent based model of vascular development predicted adverse effects of a reference anti-angiogenic thalidomide analog, 5HPP-33, on in vitro angiogenesis with respect to both concentration-response and morphological consequences. These findings support the utility of cell agent-based models for simulating a morphogenetic series of events and for the first time demonstrate the applicability of these models for predictive toxicology.
Highlights
Vascular development is a complex process regulated by biological networks that vary in topology and state across different tissues and gestational stages
We built a novel computational model of vascular development that includes multiple cell types responding to growth factor signaling, inflammatory chemokine pathways and extracellular matrix interactions
Simulated results of an anti-angiogenic thalidomide compound were highly comparable to results in an endothelial tube formation assay
Summary
Vascular development is a complex process regulated by biological networks that vary in topology and state across different tissues and gestational stages. Initial stages of blood vessel development in the embryo encompass a morphogenetic series of events from angioblast differentiation into a selforganizing endothelial cell (EC) plexus [1]. This process requires coordinate regulation of complex cellular signals and behaviors such as mitosis, migration, differentiation, adhesion, contractility, apoptosis, and extracellular matrix (ECM) remodeling. The embryonic vasculature forms through a semi-autonomous process in which EC derived from migratory angioblasts assemble into a primitive multicellular network This process, vasculogenesis, occurs at different times and locations centrally and peripherally in the embryo and is mediated by cellular processes such as differential migration, proliferation, and adhesion that may form polygonal (roughly hexagonal) whorls of endothelial cords. Further growth and remodeling through angiogenesis supports the development of tissues and organ systems through growth and expansion of the primitive vasculature network via sprouting of new capillaries, vessel stabilization and maturation, and flow-based
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