A computational model predicting disruption of blood vessel development.

Area of Science:

• * Developmental Biology
• * Computational Biology
• * Toxicology

Background:

• * Vascular development involves complex signaling networks regulating endothelial cell (EC) behavior, extracellular matrix (ECM) remodeling, and growth factor generation.
• * Simulating these intricate processes requires detailed biological information and computationally tractable models.
• * Existing models often struggle to balance biological complexity with mathematical tractability.

Purpose of the Study:

• * To develop a novel multicellular agent-based model for simulating vasculogenesis and angiogenesis.
• * To incorporate key biological pathways including vascular endothelial growth factor (VEGF) and chemokine signaling.
• * To apply the model for predictive toxicology using high-throughput screening (HTS) data.

Main Methods:

• * Utilized the CompuCell3D modeling environment for a multicellular agent-based approach.
• * Developed a semi-automatic knowledgebase for model parameterization.
• * Integrated vascular endothelial growth factor (VEGF) signals, inflammatory chemokines, and the plasminogen activating system.
• * Mapped computational model targets to in vitro chemical profiling data from EPA's ToxCast HTS dataset.

Main Results:

• * The model successfully recapitulated stereotypical capillary plexus formation and emergent cellular behaviors.
• * Demonstrated a heterologous bridging phenomenon during endothelial cord formation.
• * Predicted adverse effects of a thalidomide analog (5HPP-33) on in vitro angiogenesis, including concentration-response and morphological changes.

Conclusions:

• * Cell agent-based models are valuable tools for simulating complex morphogenetic events in vascular development.
• * This study demonstrates the utility of such models for predictive toxicology, specifically for assessing chemical impacts on angiogenesis.
• * The findings highlight the potential of computational modeling to advance our understanding of vascular biology and chemical safety assessment.