RHOMECHANOVASC · Regulation of Rho proteins by mechanical forces in the vascular system
FP7 — People (Marie Curie Actions)
- Duration
- 2010-08-01 → 2013-08-31
- EU contribution
- €213,108
- Participants
- 1
- Scheme
- MC-IOF
Lines connect the coordinator with its partners.
Results in brief
Regulation of Rho proteins by mechanical forces in the vascular system
Over the last 10 years numerous studies have revealed that cells respond to their physical environment. Cells can “sense” and convert mechanical forces into specific biochemical signals that ultimately regulate cellular processes. Our project aimed to identify the molecular mechanisms which regulate the cellular response to force and to evaluate the role of these mechanisms during cardiovascular diseases development (CVD). During the outgoing phase, we were able to accomplish the first objective of the project. By combining biochemical and biophysical approaches, we identified two GEFs, LARG and GEF-H1, as key molecules that regulate the cellular adaptation to force. We show that stimulation of integrins with tensional force triggers activation of these two GEFs and their recruitment to adhesion complexes. Surprisingly, activation of LARG and GEF-H1 involves distinct signalling pathways. Our results reveal that LARG is activated by the Src family tyrosine kinase Fyn, whereas GEF-H1 catalytic activity is enhanced by ERK downstream of a signalling cascade that includes FAK and Ras. This work was published in Nature Cell Biology (Guilluy et., Nat Cell Biol. 2011 Jun;13(6):722-7). During the return phase, we analyzed the pathophysiological relevance of LARG and GEF-H1 in the vascular system. In a collaborative work, we found that GEF-H1 regulates the endothelial response to shear stress, indicating that GEF-H1 may play a role during atherosclerosis development. Interestingly we observed that Ras, GEF-H1 upstream regulator, is activated in arteries isolated from old rats, suggesting that the mechanosensitive GEF, GEF-H1, could contribute to the vascular defects associated with age.
Data: CORDIS, © European Union
Project objective
As molecular links between mechanosensors and the regulation of cellular processes Rho proteins have a critical position in mechanotransduction. Interestingly during cardiovascular disease (CVD) involving aberrant hemodynamic forces Rho proteins are activated. How do mechanical forces regulate Rho proteins? How do they contribute to the mechanical adaptation of the cell? And How is this mechanism altered during CVD? To answer these questions we have designed a proposal in two phases with interdisciplinary approaches including biochemical assays, three dimensional force microscopy (3DFM) and in vivo analysis. 1.Outgoing phase: To determine how mechanical forces activate Rho proteins and to evaluate the involvement of Rho proteins during the mechanical adaptation to force. We will identify the mechanism of Rho proteins activation using an innovative biochemical assay developed in the host lab and we will evaluate their involvement in mechanical adaptation of the cell using 3DFM. 2.Return phase: To evaluate the pathophysiological relevance of the mechanisms identified during the first phase. We will determine the cellular functions downstream of the regulators identified during phase 1 and we will investigate their activities in two animal models of altered hemodynamic forces by using the small animal physiology core facility available in the return host. The proposed project will yield new insights in different areas of life science from fundamental cell biology to potential identification of new therapeutic targets. First the anticipated results will contribute to better understand how the cells modify their mechanical properties in response to force. This crucial mechanism is central in many aspects of biology. We will also evaluate the modulation of Rho regulators in animal models of CVD; this will permit identification of new pharmacological targets for this public health problem.
Original text from CORDIS.
Participants
- INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union