It is estimated that up to 8% of men aged over 65, and up to 2.2% of women of the same age harbour aortic aneurysms. Aneurysm rupture is estimated to be the tenth most common cause of mortality and accounts for 2% of all deaths. Moreover, although current repair and treatment strategies are effective in stabilising large aneurysms (>50mm in diameter), in-hospital mortality still represents a significant clinical problem. Additionally, the majority of AAAs detected by ultrasound are <50mm in diameter, for which there is no standardised treatment. Hence there is an urgent need to identify medical therapies for prevention or as an adjunct to intervention. Consequently, there has been a number of animal models of aneurysm developed to test potential new therapeutics, whilst also affording an insight into the pathophysiology of this debilitating disease. Indeed over 4,000 mice alone are used every year in aneurysm research. Accordingly, this research proposal aims to address the replacement remit within the NC3Rs, through the development/characterisation of a potential reproducible ex vivo human model of aneurysm, to serve as a suitable replacement for animal models of aneurysm development, progression and rupture.
To achieve this goal we aim to utilise human umbilical cord as a readily accessible supply of arterial conduit which can then be placed into a bio-reactor. We will then assess the ability of agents known to induce aneurysm formation in well-characterised mouse models, to trigger well-defined morphological and histolological changes associated with aneurysm formation, progression and rupture. This will include evaluation of the four principle characteristics associated with aneurysm formation; vascular smooth muscle (VSMC) cell phenotypic alteration; VSMC apoptosis; elastin fragmentation; and matrix metalloproteinase expression and activity. In order to validate our ex vivo model we will test interventions we have previously shown to retard aneurysm formation.