Modelling signalling pathways and cellular dynamics in vascular mechanobiology: a theoretical, experimental and computational study

Thesis

Blood vessels are dynamic structures whose properties are continuously adapted by resident vascular cells. Existing mechanobiological models tend to ignore regulatory signalling and cell population dynamics, both key determinants of arterial growth and remodelling (G&R). In this D.Phil., a combined theoretical, experimental and computational approach is used to formulate, refine and implement a novel model of the arterial wall that includes vascular mechanics, microstructure, biochemical metabolism and signalling, and cell phenotype and population dynamics.

A mathematical chemo–mechano–biological (CMB) model is formulated by coupling a biomechanical model of the arterial wall as a cylindrical nonlinear elastic membrane to a system of biologically–informed evolution laws governing fibroblast cell–mediated, transforming growth factor (TGF)-β–regulated collagen metabolism. Model simulation of inflammatory aneurysm development suggests that increasing TGF-β levels promotes a cell–driven profibrotic response leading to aneurysm stabilisation, illustrating the model’s ability to couple chemo–biological processes to tissue–level mechanical evolution.

To inform the theoretical framework experimentally, a recent mouse model of post–developmental disruption of medial smooth muscle TGF-β signalling is for the first time subjected to hypertension, and characterised by biaxial mechanical testing and (immuno)histological staining. Increased adventitial TGF-β levels following perturbation are associated with strong profibrotic responses (increased cellularity, collagen deposition, thicker walls) altering tissue mechanics (lower biaxial stress, higher structural stiffness).

Simulation of realistic arterial geometries is enabled by coupling the 1D CMB model to a three–dimensional structural solver. Heterogeneous spatial distributions of mechanical, microstructural and chemo–biological variables determining the evolution of complex saccular aneurysm geometries can be simulated with this 3D implementation.

A novel chemo–mechano–biological model of vascular cell dynamics and regulatory signalling governing arterial G&R is formulated, informed by specifically–generated experimental data, and implemented in an advanced 3D computational framework. This will allow for virtual investigation of therapies acting on chemo–biological agents of arterial G&R, with potential benefits for vascular disease patients.

Authors: Aparicio, P

• DOI: 10.5287/ora-gopq96ngo
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: aneurysm; fibroblast; TGF-beta; vascular; growth and remodelling; collagen
• Subjects: Mechanobiology; Biomechanics