Ascending Aortic Aneurysm in Angiotensin II–Infused Mice: Formation, Progression, and the Role of Focal Dissections

Objective To understand the anatomy and physiology of ascending aortic aneurysms in angiotensin II-infused ApoE(-/-) mice. Approach and Results We combined an extensive in vivo imaging protocol (high-frequency ultrasound and contrast-enhanced microcomputed tomography at baseline and after 3, 10, 18, and 28 days of angiotensin II infusion) with synchrotron-based ultrahigh resolution ex vivo imaging (phase contrast X-ray tomographic microscopy) in n=47 angiotensin II-infused mice and 6 controls. Aortic regurgitation increased significantly over time, as did the luminal volume of the ascending aorta. In the samples that were scanned ex vivo, we observed one or several focal dissections, with the largest located in the outer convex aspect of the ascending aorta. The volume of the dissections moderately correlated to the volume of the aneurysm as measured in vivo (r(2)=0.46). After 3 days of angiotensin II infusion, we found an interlaminar hematoma in 7/12 animals, which could be linked to an intimal tear. There was also a significant increase in single laminar ruptures, which may have facilitated a progressive enlargement of the focal dissections over time. At later time points, the hematoma was resorbed and the medial and adventitial thickness increased. Fatal transmural dissection occurred in 8/47 mice at an early stage of the disease, before adventita remodeling. Conclusions We visualized and quantified the dissections that lead to ascending aortic aneurysms in angiotensin II-infused mice and provided unique insight into the temporal evolution of these lesions.

Early Morphofunctional Changes in AngII-Infused Mice Contribute to Regional Onset of Aortic Aneurysm and Dissection

Lydia Aslanidou, Goran Lovric, Nikolaos Stergiopulos, Bram Trachet

Aortic aneurysms and dissections are silent and lethal conditions, whose pathogenesis remains incompletely understood. Although angiotensin II (AngII)-infused ApoE-/- mice have been widely used to study aortic aneurysm and dissection, early morphofunctional alterations preceding the onset of these conditions remain unknown. The goal of this study was to unveil early morphofunctional changes underlying the onset of aneurysm and dissection. At 3 days post-AngII infusion, suprarenal abdominal aorta presented significant volumetric dilatation and microstructural damage. Ex vivo assessment of vascular reactivity of the suprarenal dissection-prone aorta and its side branches, showed an endothelial and contractile dysfunctions that were severe in the suprarenal aorta, moderate distally, and absent in the side branches, mirroring the susceptibility to dissection of these different vascular segments. Early and specific morphofunctional changes of the suprarenal aorta may contribute to the regional onset of aortic aneurysm and dissection by exacerbating the biomechanical burden arising from its side branches.

KARGER2020

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

Lydia Aslanidou

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 wallâs 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 function changes prior to dissection. We found a regional variation: both the contractile and the endothelial function were severely compromised in the suprarenal aortaâs dissection-prone segment, but only mildly so in its dissection-protected segments. Surprisingly, vascular function was largely preserved in the adjacent side branches, creating a local discontinuity in the profile of contractile capacity between the (diseased) aorta and the (non-diseased) branches.

EPFL2019

Angiotensin II infusion into ApoE(-/-) mice: a model for aortic dissection rather than abdominal aortic aneurysm?

Lydia Aslanidou, Alessandra Piersigilli, Patrick Segers, Jessica Sordet-Dessimoz, Nikolaos Stergiopulos, Bram Trachet

Aims Angiotensin II-infused ApoE(-/-) mice are a popular mouse model for preclinical aneurysm research. Here, we provide insight in the often-reported but seldom-explained variability in shape of dissecting aneurysms in these mice. Methods and results N=45 excised aortas were scanned ex vivo with phase-contrast X-ray tomographic microscopy. Micro-ruptures were detected near the ostium of celiac and mesenteric arteries in 8/11 mice that were sacrificed after 3 days of angiotensin II-infusion. At later time points (after 10, 18, and 28 days) the variability in shape of thoraco-abdominal lesions (occurring in 31/34 mice) was classified into 7 different categories based on the presence or absence of a medial tear (31/31), an intramural hematoma (23/31) or a false channel (11/23). Medial tears were detected both in the thoracic and the abdominal aorta and were most prevalent at the left and ventral aspects of celiac and mesenteric arteries. The axial length of the hematoma strongly correlated to the total number of ruptured branch ostia (r(2) = 0.78) and in 22/23 mice with a hematoma the ostium of the left suprarenal artery had ruptured. Supraceliac diameters at baseline were significantly lower for mice that did not develop an intramural hematoma, and the formation of a false channel within that intramural hematoma depended on the location, rather than the length, of the medial tear. Conclusion Based on our observations we propose an elaborate hypothesis that explains how aortic side branches (i) affect the initiation and propagation of medial tears and the subsequent adventitial dissection and (ii) affect the variability in shape of dissecting aneurysms. This hypothesis was partially validated through the live visualization of a dissecting aneurysm that formed during micro-CT imaging, and led us to the conclusion that angiotensin II-infused mice are more clinically relevant for the study of aortic dissections than for the study of abdominal aortic aneurysms.