An Agent-Based Model of Vascular Disease Remodeling in Pulmonary Arterial Hypertension

Abstract

Abstract
We have developed a multi-scale, 3D agent-based model (ABM) of mammalian arterial blood vessels specifically focusing on the pathobiology of pulmonary arterial hypertension (PAH), a disease that may involve pathologies in any of the various signaling pathways, cell types, layers, or connective structures in blood vessel walls.
Model and Methods
PAH is characterized by vessel remodeling that includes thickening and stiffening of pulmonary arterial vessels at multiple scales, neo-muscularization of vessels, lesion formation, and vessel obliteration, all contributing to a significantly increased resistance to blood flow which results in increased pressures in the lung circulation. The complexity of vessel structure has limited the study of vascular tissue to experimental in vitro studies of monolayers of individual cell types, or to using artificially induced disease in animal models that do not adequately represent the disease process in humans, thus many questions about the pathophysiology of PAH remain unanswered. To help address the significant gap in knowledge of mechanisms of vascular disease, we have developed a multi-scale, 3D spatial agent-based model of mammalian arterial blood vessels and have focused our attention on the pathobiology of PAH.
We investigate the effects of two important intercellular signaling pathways, bone morphogenic protein (BMP) and interleukin-6 (IL-6), on tissue remodeling in a 3D scale ABM of the mammalian artery. The agent types in the model directly reflect the cell populations and morphology of the vascular wall and the signaling models are developed from behavioral observations of selected cell types from the experimental literature. An overview of the simulation environment and capabilities followed by a model description will provide the basis for the model that maps physiological concepts to computational components. We will present the results of signaling parameter space exploration and discuss the findings.

Results
Simulation tools provide a useful alternative for exploring underlying cellular behaviors and their impact on tissue function since current laboratory experimental procedures for vascular tissue cannot sufficiently replicate the vascular wall structure and since histological specimens of diseased tissue only provide a static snapshot of the pathophysiology. The results of the parameter sweep experiments for BMP and IL-6 inflammatory signaling lead to several ideas with potentially relevant clinical and experimental implications.
A series of images from the graphical rendering of a cross sectional slice of the 3D tissue volume illustrates this process of vascular wall remodeling over a 25 week period for the simulation of combined BMP signaling dysregulation together with the inflammatory response due to IL-6 emission by resident fibroblasts, resulting in SMC over proliferation, inflammatory infiltrates, medial layer thickening, wall thickening, and a reduction in lumen area. (Figure 1). Asymmetrical remodeling of the vessel wall is evident due to T-cell and fibroblast infiltration of the adventitia via the vasa vasorum. Since the vasa vasorum network structure is typically not uniform in the vessel wall, it is only natural that remodeling processes due to trafficking via the vasa vasorum should be dependent on its network structure.