Because changes in the organization and composition of extra-cellular matrix can have consequences on mechanical properties of the arterial wall, understand mechanisms of maturation of the elastin and collagen, (maines extra-cellular proteins) is important.
Vascular smooth muscle cells highly express vascular adhesion protein 1 (VAP-1), which display a semicarbazide-amine oxidase (SSAO) activity. Studies using pharmacological inhibitors of SSAO have been previously suggested that SSAO could be important for the arterial wall organization, without excluding that a part of the affects was due to lysyl oxidase inhibition. Lysyl oxydase is the main enzyme establishing cross-links in or between elastin and collagan until now.So I will study tha SSAO role in arterial wall, comparing arteries from wild type, VAP-1 knockout mice (establishment by the host) and VAP-1 knouckhout mice over-expressing VAP-1 in smooth muscles (will established during this project).
Histomorphometry and immunohistochemistry will be used to evaluate the arterial morphology and organization, content in elastin and collagen will also be measured. Arterial mechanical properties will be evaluated in vivo with eckotracking and mechanical resistance will be tested in vitro with the collaboration of Lacolley's laboratory. Moreover, because endogenous substrate of VAP-1/SSAO are not known, I will search whether SSAO from vascular smooth muscle cells is able to oxidize directly amine moiety in elastin and collagen to cross-link these molecules.
Then, I will verify whether SSAO activity can regulate vascular smooth muscle cells phenotype and expression of extra-cellular matrix proteins. VAP-1/SSAO expression will be measured in function of quality and quantity of extra-cellular matric
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