Modifications de la matrice extracellulaire dans la rigidité artérielle
Within the vascular wall, endothelial cells, vascular smooth muscle cells and fibroblasts are surrounded by a complex and structured network of secreted macromolecules and proteins, the extracellular matrix. Reciprocal interactions between matrix and cells are essential to growth, development and remodeling. However, in pathological situations, the alteration of these interactions can lead to the development of different disease states. With aging, the extracellular matrix of large elastic arteries undergoes several modifications. The elastic lamellae are fragmented or degraded and calcify, whereas more rigid proteins, such as collagen, accumulate and cause fibrosis. These alterations are associated with the stiffening of arteries, which results in the development of isolated systolic hypertension. In order to study the sequence of events occuring in the development of this pathology, we used an animal model of calcification based on the inhibition of a matrix Gla protein, which physiologically prevents calcification, with warfarin. We observed an acute and transient activation of MMP-9 and TGF-ß, which preceded the phenotypic modulation of vascular smooth muscle cells, calcification and changes to hemodynamic parameters. Moreover, the inhibition of MMPs and TGF-ß prevented vascular calcification. We also studied the role of an extracellular matrix enzyme, transglutaminase 2, in the development of vascular calcification associated with isolated systolic hypertension. Using a novel inhibitor of this enzyme, we established a key role for transglutaminase 2 in this pathological process. This thesis demonstrates the relevance of directly targeting the extracellular matrix, particularly MMP-9, TGF-ß and transglutaminase 2, as a novel therapeutic avenue in the treatment of isolated systolic hypertension.
Calcification Transglutaminase MMP TGF-beta Extracellular Matrix Isolated systolic hypertension Calcification Arterial stiffness Transglutaminase MMP TGF-beta