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.

It is known that there are many cardiovascular diseases caused by the alterations in the blood vessels, that affect most of the world population. The knowledge of the mechanobiological behavior of blood vessels is used for understanding how cardiovascular diseases could affect the human body. So, by studying the growth and remodeling (G&R) of the arterial tree, it is possible to predict how these diseases will develop and consequently, how they can be treated or even prevented. The human body naturally tries to find the optimum steady-state by changing either the production of the constituents of the arteries or the flow rate through blood vessels. This effect is the phenomenon that is going to be studied in this thesis and these three main factors have to be taken into account when reproducing the diseases’ effects: the so-called transmural pressure, the blood flow rate, and the biomechanics of the constituents which form the arterial wall. Therefore, through numerical simulations the variation of these factors can be predicted, although always with a reliability supported by experimental data. / Se sabe que hay muchas enfermedades cardiovasculares causadas por alteraciones en los vasos sanguíneos que afectan gran parte de la población mundial. El conocimiento del comportamiento mecanobiológico de los vasos sanguíneos se usa para entender cómo estas enfermedades puede afectar al cuerpo humano. Así, estudiando el crecimiento y desarrollo (G&R) del árbol arterial, es posible predecir cómo estas enfermedades se van a desarrollar y consecuentemente, cómo pueden tratarse o incluso prevenirse. El cuerpo humano tiende a buscar un estado de equilibrio óptimo de forma natural cambiando o bien la producción de los constituyentes de las arterias o bien el flujo de sangre que atraviesa los vasos sanguíneos. Este efecto es el fenómeno que va a ser estudiado en esta tesis y se ha de tener en cuenta tres factores principales cuando se quiere reproducir los efectos de dichas enfermedades: la presión transmural, el flujo de sangre y la biomecánica de los constituyentes que forman la pared arterial. Luego, a través de simulaciones numéricas la variación de estos factores puede ser predicha, aunque siempre con una veracidad aportada por datos experimentales. / Vascular occlusion, modelling, arteries, arterial tree, growth and remodelling, Murray, cerebrocardiovascular diseases, adaptation, thrombosis, calcification, anemia, polycythemia, isquemia, edema