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From mechanical stress to vascular fate

Periodic Reporting for period 4 - MechanoFate (From mechanical stress to vascular fate)

Reporting period: 2020-07-01 to 2021-06-30

Within the wall of blood vessels, cells are tightly regulated by their mechanical environment. Physiological mechanical stress defines and stabilizes vascular cell phenotype, while aberrant mechanical signals trigger phenotypic alteration, leading to inflammation, vascular remodeling and cardiovascular disease development. Whereas cardiovascular diseases cause more than half of all deaths across the European region, how mechanical cues impact vascular wall cell phenotype remains poorly understood. In order to elucidate the molecular mechanisms that regulate vascular cell phenotype in response to mechanical stress, we designed an interdisciplinary proposal which gathers biophysical, biochemical and genetic assays, with the following objectives: I) To determine how nuclear mechanotransduction pathways regulate vascular cell phenotype in response to mechanical cues. II) To identify the molecular mechanisms which protect resident vascular stem cells from mechanical stress-induced differentiation.
Completion of this project allowed us to identify several new nuclear mechanotransduction mechanisms which contribute to regulate gene expression and genome organization in vascular cells. Our work indicates that these force-activated signaling pathways are major regulators of cell growth and may constitute potential new therapeutic targets in cardiovascular and regenerative medicine.
During the first part of the project, we have identified several nuclear proteins which contribute to mechanotransduction and trigger signaling pathways in response to mechanical tension. After evaluating the impact of these nuclear proteins on gene expression and genome organization, we made two major observations: (1) Our work demonstrates that the inner nuclear membrane contains mechanosensitive proteins, whose activity and/or interactions are regulated by mechanical forces transmitted to the nucleus. (2) These proteins regulate gene expression and cell cycle progression in response to mechanical stress.
In the second part of this project, we identified cytoskeletal proteins that are only expressed in resident vascular stem cells and not in more differentiated cells of the vascular wall. Among these candidates, we identified a protein associated with actin filaments that is necessary for stretch-induced differentiation into smooth muscle cells.
The MechanoFate project has allowed the identification of novel mechanosensitive pathways that control vascular cell growth and differentiation. We anticipate that these signaling pathways may constitute new therapeutic targets in cardiovascular medicine to prevent or limit pathological vascular remodeling.