The onset of cardiovascular disease in mice: an image-based, computational-experimental approach

In a number of cardiovascular diseases, the paucity of longitudinal human data hinders our understanding of disease evolution and forestalls the discovery of new therapeutic strategies. We therefore heavily rely on animal models to elucidate the mechanisms that govern disease development. Nonetheless, the reference mouse arterial physiology and hemodynamics of its systemic circulation have yet to be described. But preclinical research is not limited to healthy mice; it helps decode the elusive etiology of potentially deadly pathologies such as aortic aneurysms and dissections. A key question is: Why are these pathologies so location-specific? In humans, abdominal aortic aneurysms affect the infrarenal aorta and aortic dissections form in the thoracic aorta. Inversely, in the most commonly used mouse model of this field, aortic dissections preferentially form in the suprarenal abdominal aorta but reasons for such localization remain unknown in humans and mice. In Chapter 1 we aimed to fill the knowledge gap of mouse hemodynamics, by translating an existing 1D model of the human arterial circulation to the healthy mouse. The model combines a broad range of literature data with a detailed description of the murine vasculature. Model predictions of pressure and flow were validated against pressure, velocity and diameter measurements from a large independent dataset of mice. This versatile tool can be used to simulate pathology and facilitate the implementation of the 3R's principle in research practice. Our next steps aimed to unravel the origins of site-specific aortic dissections in the mouse model of Angiotensin II infusion. Initially, we imaged the inceptive stage of disease to understand what happens in the suprarenal mouse aorta. Then, we explored why both from a biomechanical and a mechanobiological standpoint. In Chapter 2, we use high-resolution synchrotron imaging to characterize the early morphology of the suprarenal aorta in mice infused with Angiotensin II, prior to overt dissecting events. We found that the primary damage of the wallâ s microstructure preferentially occurs around two major side branches of the aorta. After evidence of this direct involvement of side branches in disease onset, we investigated the underlying reasons from two distinct perspectives. In the synchrotron-based computational study of Chapter 3, we hypothesized that biomechanical forces expose branching sites to early vascular injury. We used an in-house framework which enables a. computational structural mechanics of the aortic wall using mouse-specific geometries, and b. mouse-specific validation to indicate whether high mechanical strain spatially coincides with microstructural defects. Branch-related hotspots of strain co-localized with early damaged microstructure, thus pointing towards a mechanically-driven mechanism that nucleates around the aortic branches. In Chapter 4 we explored from a mechanobiological perspective if the suprarenal aorta's vascular