Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - MechanoFate (From mechanical stress to vascular fate)

Teaser

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...

Summary

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.

Work performed

Since the beginning of the project, we have made some substantial progress towards reaching both objectives one and two. Regarding the first objective, we have identified a list of molecular candidates involved in nuclear mechanotransduction pathways by using distinct mechanical stimulations and proteomics approaches. Among these candidates are nucleoskeletal proteins, including proteins that are anchored in the inner nuclear membrane, transcription factors and nucleoplasmic proteins. In addition, we evaluated the involvement of these candidates in regulating gene expression in response to stretch and we achieved two main results: (1) Our work demonstrates that the inner nuclear membrane contains some mechanosensitive proteins whose stability is force dependent. (2) We found that mechanical tension affect inner nuclear membrane protein expression, which in turn activate transcription factors and promote cell growth.
Concerning the second objective, we completed the first step and we identified 22 molecular candidates that are only expressed in resident vascular stem cells and not in more differentiated cells of the vascular wall. We started investigating their potential role during mechanical stress transmission and/or transduction in response to stretch.

Final results

So far the project has allowed the identification of new mechanosensitive pathways that influence vascular cell growth and differentiation and we anticipate new results for both objectives until the end of this project. Regarding the objective 1, we will identify epigenetic mechanisms regulated by mechanical stress and explore how these can contribute to cardiovascular development. The completion of the objective 2 will allow us to narrow the list of specific vascular stem cell regulators and may yield the identification of new therapeutic targets in cardiovascular medicine and help the differentiation of vascular tissue in vitro. Within the framework of this project, we also started developing a new method to study cell mechanics in multicellular structures containing a population of distinct vascular cells. We anticipate completing the development of this method within the next year.