Our team is interested in the molecular aging of matrix macromolecules (in particular collagen and elastin) and its role in the remodeling of vascular wall. Molecular aging is defined as the alterations that proteins undergo during their biological life. These alterations are of two types, either additive reactions (e.g. oxidation, glycation, carbamylation) or cleavages (proteolytic or not). Whatever their nature, these discrete events accumulate over time and contribute to the progressive modification of the structural and functional properties of proteins. Our team addresses this issue through the following three research axes:
Axis 1: Characterization of vascular matrix aging
Matrix proteins have long half-lives (collagen: 20 years / elastin: 70 years) and are therefore greatly exposed to molecular aging. The objective of this axis is to analyze matrix aging at the molecular level by studying non-enzymatic post-translational modifications (mainly carbamylation and glycation) and proteolysis of matrix elastic fibers with a focus on vascular aging. Our work has enabled us to demonstrate the accumulation of carbamylation products in tissues during aging. The objective of this axis is also to understand how the aging of matrix proteins can impact their structural and mechanical properties. For instance, analyses of aorta sections by atomic force microscopy (AFM) allow us to evaluate the stiffness of elastic fibers.
Axis 2: Physiopathological consequences of vascular matrix aging
The aging of matrix proteins has an impact at the molecular level but also at the tissue level. This axis aims at analyzing the physiopathological consequences of matrix aging in various physiopathological situations characterized by an accelerated aging of the vascular system. We use in vivo mice models of type 2 diabetes and chronic renal failure, two pathological contexts characterized by an accelerated vascular aging accompanied by complications such as atherothrombosis and aneurysm formation. For example, our research projects are focused on the study of the influence of elastin proteolysis in the inflammatory reaction at the level of monocyte/macrophage polarization during atherosclerosis, the role of the RAGE receptor in the vascular calcification process induced by elastin peptides or the role of carbamylation of vascular matrix proteins in the development of aortic aneurysm.
Axis 3: Receptors, signaling and pharmacological approaches
In addition to the mechanical defects it induces, matrix aging can regulate cell function through different receptors and thus participate in functional alterations of vessels. The receptors on which the team focuses are the receptor for advanced glycation products (RAGE) and the elastin receptor complex. Our overall strategy is (i) to characterize the receptors at the molecular level (nature, structure of the receptor, ligands, partners), (ii) to decipher the signaling pathways they control when engaged in matrix aging (identification of key signaling checkpoints), and (iii) to propose, if necessary, innovative strategies to block their deleterious effects.