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. The proposed project will yield new insights in different areas of life science from cell biology to potential identification of new therapeutic targets in cardiovascular and regenerative medicine.