Aneurysm rupture is a common cause of premature mortality in the UK. Aneurysms are caused by the deterioration and weakening of artery walls resulting in vessel dilation that is asymptomatic before rupture. Although surgical treatments for ruptured and non-ruptured aneurysms (≥50 mm diameter) are often successful, the major issue is getting the patient to hospital in time. At present, there are no standardised treatments for patients with non-ruptured aneurysms ≤50 mm in diameter. Mouse models are currently used to study aneurysm formation but mice can suffer from aortic dissection and subsequent sudden death.
Why we funded it
This PhD Studentship aims to replace the need for mice in the study of aneurysm development, progression and rupture by using arterial conduits from human umbilical cords to develop an ex vivo human model.
Within Dr Johnson’s laboratory three models of aneurysm formation are used across four projects. 180 mice are used per project, which if replaced with a reproducible and well validated ex vivo human model would be a substantial saving in animal use. A literature search showed 835 original articles using mouse models of aneurysm have been published in the last five years. On average the publications use nine mice per experimental group and three experimental groups, equating to approximately 22,545 mice used for aneurysm studies in the past five years.
Arterial conduits will first be exposed to aneurysm-inducing agents, introduced intraluminally, before the conduits are placed in a bioreactor. Laminar or directional flow will then be applied to the artery inducing the formation of a diffuse concentric or localised eccentric aneurysm. The length of the human umbilical artery allows for experiments to be conducted in paired analyses, aiding statistical analysis. Morphometrical analysis will be performed on histological samples from baseline and aneurysm induced arterial conduits collected at multiple timepoints. The model will be optimised by a dose response analysis to assess the ability of the aneurysm-inducing agents to cause structural and biological changes associated with aneurysm formation, progression and rupture. These include the effects on vascular smooth muscle cell (VSMC) apoptosis, VSMC cell phenotypic alteration, elastin fragmentation and matrix metalloproteinase expression and activity. Interventions known to slow aneurysm progression in animal models will be evaluated for effectiveness in the ex vivo model and validated by comparing with results from mouse tissue from previous in vivo studies and human aneurysm samples from the tissue BioBank.
Bianco R et al. (2020). A Protocol for a Novel Human Ex Vivo Model of Aneurysm. STAR Protocols doi: 10.1016/j.xpro.2020.100108
Fasolo F et al. (2019). Non-coding RNAs in cardiovascular cell biology and atherosclerosis. Cardiovascular Research 115(12):1732-1756. doi: 10.1093/cvr/cvz203