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Rôle de la fibrilline-1 dans la fonction cardiovasculaire au cours du vieillissement : signalisation de la fibrilline-1 dans les cellules endothéliales humaines et exploration structurale et fonctionnelle chez les souris Fbn-1+/mgΔ.

Abstract : Fibrillin-1, the main component of microfibrils and second main component of elastic fibers, is a glycoprotein whose gene mutation in human is responsible for Marfan syndrome, characterized at the vascular level by aortic aneurysm and dissections. In this work, we investigated on the one hand, the role of fibrillin-1 in human endothelial cell physiology and, on the other hand, the effect of fibrillin-1 quantitative deficiency on the structure and function of the cardiovascular system during aging in mice. Fibrillin-1 fragment "PF14" induced calcium signaling through α5β1 and αvβ3 integrins, phospholipase C activation and intracellular calcium store mobilization, as well as endothelial cell proliferation and migration. Fibrillin-1 severe or full deficiency leads to premature lethality (within two weeks postnatal) in mice, while partial deficiency, through fibrillin-1 heterozygous hypomorphic deletion of exons 19 to 24 (mgΔ deletion), does not affect mice longevity. Fbn-1+/mgΔ mice were hypotensive with cardiac hypertrophy and presented aortic aneurysm becoming more frequent in aged animals. The aortic wall of Fbn-1+/mgΔ mice presented structural (elastic fibers fragmentations), biomechanical (increased aortic stiffness) and vasomotor alterations. This work suggests that fibrillin- 1 quantitative deficiency may alter the signaling events normally triggered by this protein in endothelial cells during vascular morphogenesis, and subsequently induce aneurysms in the aorta wall during ageing. The opposite effects of fibrillin-1 and elastin deficiencies suggest opposite roles for these two major components of elastic fibers. Moreover, this work validates Fbn-1+/mgΔ mice as a structural and functional model for Marfan syndrome.
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https://tel.archives-ouvertes.fr/tel-00711832
Contributor : Boubacar Mariko <>
Submitted on : Tuesday, June 26, 2012 - 10:56:25 AM
Last modification on : Friday, November 6, 2020 - 4:12:17 AM

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  • HAL Id : tel-00711832, version 1

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Boubacar Mariko. Rôle de la fibrilline-1 dans la fonction cardiovasculaire au cours du vieillissement : signalisation de la fibrilline-1 dans les cellules endothéliales humaines et exploration structurale et fonctionnelle chez les souris Fbn-1+/mgΔ.. Physiologie [q-bio.TO]. Université Joseph-Fourier - Grenoble I, 2009. Français. ⟨tel-00711832⟩

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