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Final Activity Report Summary - VAP1 IN ARTERIES (Role of VAP-1/SSAO in arterial wall physiology)

Arterial function is to absorb the variations of the arterial blood pulse pressure at the heart and to transform it into a continuous blood flow. Because changes in the organisation and composition of the arterial wall can have consequences on its mechanical properties and lead to aneurysms, dissections and ruptures, it is important to understand how proteins interact together. The most important proteins forming this matrix are elastin and collagen. Until now, the lysyl oxidase (LO) is the principal enzyme establishing links in or between elastin and collagen. But recently, another enzyme was suspected to be involved in these processes. This enzyme is called 'vascular adhesion protein-1' (VAP-1) or 'semicarbazide-sensitive amine oxidase' (SSAO) and produces molecules highly reactive and harmful. Its functions are not well understood yet.

The goal of this project was to evaluate the role of this enzyme in the arterial wall using mice lacking VAP-1 / SSAO (SSAO-/- mice), recently established by Jalkanen's group. This was the first functional study of arteries lacking SSAO. Neither the arterial blood pressure nor the mechanical properties (stiffness and the mechanical strength) of large arteries in SSAO-/- mice were modified compared to wild type mice. Nevertheless, the diameter of the carotid artery was significantly higher in SSAO-/- mice suggesting that VAP-1/SSAO might contribute to arterial remodeling which occurs in some human aneurismal diseases. The morphology of the elastin network, the elastin and collagen content were identical in the two groups. The contraction and dilatation properties of arteries were unchanged in SSAO-/- mice. No change in aortic lysyl oxidase (LO) activity was detectable, indicating that SSAO invalidation is not accompanied by a compensatory increase in LO activity. Elastin does not seem to be oxidised by SSAO. Our results indicate that the lack of SSAO in mice modifies arterial geometry but does not influence mechanical properties. However, these results argue against the hypothesis that SSAO interferes in elastic fibre organisation, elastin cross-linking processes and vasoreactivity.

The microarray analysis shows that some genes coding for lipid metabolism, immunity system and endothelial factors were modified suggesting that the lack of VAP-1/SSAO might protect against the development of atherosclerosis and this proposal gave rise to new research. To assess better this question, we mated APOE mice prone to develop atherosclerosis with SSAO-/- mice to generate APOE SSAO-/- mice. We hope soon to be able to answer the following question: does the absence of SSAO reduce the development of atherosclerosis in APOE mice?

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